Heteroaryl compounds as IRAK inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application62/082,231, filed on Nov. 20, 2014, the contents of which areincorporated in its entirety by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention provides for compounds of Formula (I) as IRAKinhibitors and their use in the treatment of cancer, and other diseasesrelated to IRAK overexpression, including rheumatoid arthritis, systemiclupus erythematosus or lupus nephritis.

BACKGROUND OF THE INVENTION

Kinases catalyze the phosphorylation of proteins, lipids, sugars,nucleosides and other cellular metabolites and play key roles in allaspects of eukaryotic cell physiology. Especially, protein kinases andlipid kinases participate in the signaling events which control theactivation, growth, differentiation and survival of cells in response toextracellular mediators or stimuli such as growth factors, cytokines orchemokines. In general, protein kinases are classified in two groups,those that preferentially phosphorylate tyrosine residues and those thatpreferentially phosphorylate serine and/or threonine residues.

Kinases are important therapeutic targets for the development ofanti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology21, 1-8), for example kinases that are involved in the orchestration ofadaptive and innate immune responses. Kinase targets of particularinterest are members of the IRAK family.

The interleukin-1 receptor-associated kinases (IRAKs) are criticallyinvolved in the regulation of intracellular signaling networkscontrolling inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7).IRAKs are expressed in many cell types and can mediate signals fromvarious cell receptors including toll-like receptors (TLRs). IRAK4 isthought to be the initial protein kinase activated downstream of theinterleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) exceptTLR3, and initiates signaling in the innate immune system via the rapidactivation of IRAK1 and slower activation of IRAK2. IRAK1 was firstidentified through biochemical purification of the IL-1 dependent kinaseactivity that co-immunoprecipitates with the IL-1 type 1 receptor (Caoet al., 1996. Science 271(5252): 1128-31). IRAK2 was identified by thesearch of the human expressed sequence tag (EST) database for sequenceshomologous to IRAK1 (Muzio et al., 1997. Science 278(5343): 1612-5).IRAK3 (also called IRAKM) was identified using a murine EST sequenceencoding a polypeptide with significant homology to IRAK1 to screen ahuman phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNAlibrary (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4was identified by database searching for IRAK-like sequences and PCR ofa universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA99(8):5567-5572).

Mice that express a catalytically inactive mutant of IRAK4 instead ofthe wild-type kinase are completely resistant to septic shock triggeredby several TLR agonists and are impaired in their response to IL-1.Children who lack IRAK4 activity due to a genetic defect suffer fromrecurring infection by pyogenic bacteria. It appears that IRAK-dependentTLRs and IL-1Rs are vital for childhood immunity against some pyogenicbacteria but play a redundant role in protective immunity to mostinfections in adults. Therefore IRAK4 inhibitors may be useful for thetreatment of chronic inflammatory diseases in adults without making themtoo susceptible to bacterial and viral infections (Cohen, 2009. CurrentOpinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors have beendeveloped (Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60).IRAK1 is essential for the TLR7-mediated and TLR9-mediated activation ofIRF7 and the production of interferon-alpha (IFN-α) suggesting thatIRAK1 inhibitors may be useful for the treatment of Systemic lupuserythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays arole in proinflammatory cytokine production. Therefore IRAK2 inhibitorsmay be useful for inflammatory diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of Formula (I):

and pharmaceutically acceptable derivatives, solvates, salts, hydratesand stereoisomers thereof.

In another aspect, the invention provides compounds of Formula (I) whichare suitable for the treatment and/or prevention of disorders related toIRAK. In another aspect, the invention provides compounds which are ableto modulate, especially inhibit the activity or function of IRAK indisease states in mammals, especially in humans.

According to another aspect of the invention are provided methods forthe treatment and/or prevention of disorders selected from auto-immune,inflammatory disorders, cardiovascular diseases, neurodegenerativedisorders, bacterial and viral infections, allergy, asthma,pancreatitis, multi-organ failure, kidney diseases, plateletaggregation, cancer, transplantation, sperm motility, erythrocytedeficiency, graft rejection, lung injuries, respiratory diseases andischemic conditions.

According to another aspect, the present invention provides compounds ofFormula (I) which are selective for IRAK-4 and/or IRAK-1.

According to another aspect, the present invention provides compounds ofFormula (I) which are selective for IRAK-4 and IRAK-1.

According to another aspect the invention provides a kit or a setcomprising at least one compound of Formula (I), preferably incombination with immunomodulating agents.

Preferably, the kit consists of separate packs of:

(a) an effective amount of a compound of the formula (I) and/orpharmaceutically usable derivatives, solvates, salts, hydrates andstereoisomers thereof, including mixtures thereof in all ratios, and

(b) an effective amount of a further medicament active ingredient.

According to another aspect the invention provides a process for thesynthesis of compounds of Formulae (I).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain aspects, the present invention provides for inhibitors ofIRAK. In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

and

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which is optionallysubstituted with R^(∘); —CH═CHPh, which is optionally substituted withR^(∘); —(CH₂)₀₋₄(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R; —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionally substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(•),-(haloR^(•)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂;—O(haloR^(•)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(•), —(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃,—C(O)SR^(•), —(C₁₋₄ straight or branched alkylene)C(O)OR^(•), or—SSR^(•) wherein each R^(•) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(•) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, CI 6 aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O-alkyl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocyclic,

—C(O)-alkyl, —C(O)-alkenyl, —C(O)-alkynyl, —C(O)-carbocyclyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH-alkyl, —CONH-alkenyl, —CONH-alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂-alkyl, —OCO₂-alkenyl, —OCO₂-alkynyl, —OCO₂-carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH-alkyl,—OCONH-alkenyl, —OCONH-alkynyl, —OCONH-carbocyclyl, —OCONH-aryl,—OCONH-heteroaryl, —OCONH-heterocyclyl,

—NHC(O)-alkyl, —NHC(O)-alkenyl, —NHC(O)-alkynyl, —NHC(O)-carbocyclyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl, —NHCO₂-alkyl,—NHCO₂-alkenyl, —NHCO₂-alkynyl, —NHCO₂-carbocyclyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocyclyl, —NHC(O)NH₂, —NHC(O)NH-alkyl,—NHC(O)NH-alkenyl, —NHC(O)NH-alkenyl, —NHC(O)NH-carbocyclyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocyclyl, NHC(S)NH₂,—NHC(S)NH-alkyl, —NHC(S)NH-alkenyl, —NHC(S)NH-alkynyl,—NHC(S)NH-carbocyclyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH-alkyl,—NHC(NH)NH-alkenyl, —NHC(NH)NH-alkenyl, —NHC(NH)NH-carbocyclyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocyclyl,—NHC(NH)-alkyl, —NHC(NH)-alkenyl, —NHC(NH)-alkenyl,—NHC(NH)-carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH-alkyl, —C(NH)NH-alkenyl, —C(NH)NH-alkynyl,—C(NH)NH-carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocyclyl,

—S(O)-alkyl, —S(O)-alkenyl, —S(O)-alkynyl, —S(O)-carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH-alkyl,—SO₂NH-alkenyl, —SO₂NH-alkynyl, —SO₂NH-carbocyclyl, —SO₂NH-aryl,—SO₂NH-heteroaryl, —SO₂NH-heterocyclyl,

—NHSO₂-alkyl, —NHSO₂-alkenyl, —NHSO₂-alkynyl, —NHSO₂-carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S-alkyl, —S-alkenyl, —S-alkynyl, —S-carbocyclyl,—S-aryl, —S-heteroaryl, —S-heterocyclyl, or methylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

There is furthermore intended that a compound of the formula I includesisotope-labeled forms thereof. An isotope-labeled form of a compound ofthe formula I is identical to this compound apart from the fact that oneor more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labeled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the formulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labeled compound. Higher metabolic stability translates directlyinto an increased in vivo half-life or lower dosages, which under mostcircumstances would represent a preferred embodiment of the presentinvention. An isotope-labeled compound of the formula I can usually beprepared by carrying out the procedures disclosed in the synthesisschemes and the related description, in the example part and in thepreparation part in the present text, replacing a non-isotope-labeledreactant by a readily available isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favorable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favorable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in IRAK activity between a samplecomprising a compound of the present invention, or composition thereof,and IRAK, and an equivalent sample comprising IRAK, in the absence ofsaid compound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

or a pharmaceutically acceptable salt thereof, wherein:

-   X is CR or N;-   A is O, S, SO₂, SO, —NRC(O), —NRSO₂, or N(R); or A is absent;-   R³ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂; or-   when A is —NRC(O), —NRSO₂, or N(R); then R and R³, together with the    atoms to which each is attached, may form a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur; each of which is optionally substituted;-   X′ is CR or N;-   Ring Z is a 3-7 membered heterocylic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   R¹ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   R^(a) is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,    —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,    —NRSO₂R, or —N(R)₂;-   Ring Y is an optionally substituted 5-6 membered monocyclic    heteroaryl ring having 2-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   R^(b) is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,    —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,    —NRSO₂R, or —N(R)₂;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   wherein when X is N and A is absent, then R³ is not H.

In certain embodiments, X is CR. In certain embodiments, X is CH. Incertain embodiments, X is N.

In certain embodiments, A is O or N(R). In certain embodiments, A is O.In certain embodiments, A is N(R). In a further embodiment, A is NH orN-Me.

In certain embodiments, A is absent.

In certain embodiments, A is absent when R³ is alkyl or substitutedalkyl.

In certain embodiments, A is N(R), and the ring formed by R and R³ is a3-7 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R³ is —R, -haloalkyl, —C(O)R, —CO₂R, or—C(O)N(R)₂.

In certain embodiments, R³ is —H.

In certain embodiments, R³ is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R³ is methyl, ethyl, ethyl, propyl, i-propyl,butyl, s-butyl, t-butyl, straight or branched pentyl, or straight orbranched hexyl; each of which is optionally substituted.

In certain embodiments, R³ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R³ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, tetrahydrofuran, piperidine, piperidin-one, spiroheptane, orbicyclohexane; each of which is optionally substituted.

In certain embodiments, -A-R³ is —H, —CH₃, —CF₃,

In certain embodiments, X′ is CR. In certain embodiments, X′ is CH. Incertain embodiments, X′ is N.

In certain embodiments, Ring Z is a 3-7 membered heterocylic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted;

In certain embodiments, Ring Z is:

wherein X is O, S or NR¹; Y is C or N; and T is C or N.

In certain embodiments, Ring Z is tetrahydrofuran, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, isothiazolyl,isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl-; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, thiazolyl, thienyl, triazinyl, thiadiazole, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which isoptionally substituted.

In certain embodiments, Ring Z is a pyrazole ring.

In certain embodiments, R¹ is —R, halogen, -haloalkyl, —OR, —SR, —CN,—NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,—NRSO₂R, or —N(R)₂.

In certain embodiments, R¹ is —R.

In certain embodiments, Ring Z is

In certain embodiments, R^(a) is absent.

In certain embodiments, R^(a) is OR, CF₃, Hal, or NO₂.

In certain embodiments, Ring Y is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, Ring Y is tetrahydrofuran, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, isothiazolyl,isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, thiazolyl, thienyl, triazinyl, thiadiazole, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which isoptionally substituted.

In certain embodiments, Ring Y is an optionally substituted pyridyl,pyrazole or thiadiazole.

In certain embodiments, Ring Y is an optionally substituted pyrazole.

In certain embodiments, Ring Y is an optionally substituted thiadiazole.

In certain embodiments, Ring Y is an optionally substituted pyridyl.

In certain embodiments, R² is —R, —OR, —SR, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R² is —R, —C(O)R, —CO₂R, —C(O)N(R)₂, or —N(R)₂.

In certain embodiments, R^(b) is absent. In certain embodiments, R^(b)is an optionally substituted C₁₋₆ aliphatic, C(O)NR₂, or COR.

In certain embodiments, Ring Y is

In certain embodiments, each of Ring Z, Ring Y, R¹, R², R³, R^(a),R^(b), A, X, and X′, is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-a,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,R², R³, R^(a), R^(b), A, X, and X′, is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-b,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,R², R³, R^(a), R^(b), A, and X′, is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-c,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Y,R², R³, R^(a), R^(b), A, and X′, and m is as defined above and describedin embodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-d,

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,A, and X′, is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-e,

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,A, and X′, is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-f,

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,A, and X′, is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound selected fromTable 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen (e.g.,

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with the schemes provided in the Examples below.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit IRAK, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit IRAK, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally, intraperitoneally or intravenously. Sterile injectable forms ofthe compositions of this invention include aqueous or oleaginoussuspension. These suspensions are formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that areemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this are mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

The present invention furthermore relates to a method for treating asubject suffering from an IRAK related disorder, comprisingadministering to said subject an effective amount of a compound offormula I and related formulae.

The present invention preferably relates to a method, wherein the IRAKassociated disorder is an autoimmune disorder or condition associatedwith an overactive immune response or cancer. The present inventionfurthermore relates to a method of treating a subject suffering from animmunoregulatory abnomality, comprising administering to said subject acompound of formula (I), and related formulae in an amount that iseffective for treating said immunoregulatory abnormality.

The present invention preferably relates to a method wherein theimmunoregulatory abnormality is an autoimmune or chronic inflammatorydisease selected from the group consisting of: allergic diseases,amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Gravesophthalmopathy and asthma.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is bone marrow or organ transplantrejection or graft-versus-host disease.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is selected from the group consisting of:transplantation of organs or tissue, graft-versus-host diseases broughtabout by transplantation, autoimmune syndromes including rheumatoidarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis,multiple sclerosis, systemic sclerosis, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, parkison diseases, trauma, andchronic bacterial infection.

In certain embodiments, disorders associated with IRAK are selected fromRheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, SystemicLupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis,Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type Idiabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Diseaseand Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic feversyndrome, Cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still'sdisease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis,Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1Receptor Antagonist), Alzheimer's disease, Parkinson's disease, andCancer.

In certain embodiments, the cancer is selected from carcinoma, lymphoma,blastoma (including medulloblastoma and retinoblastoma), sarcoma(including liposarcoma and synovial cell sarcoma), neuroendocrine tumors(including carcinoid tumors, gastrinoma, and islet cell cancer),mesothelioma, schwannoma (including acoustic neuroma), meningioma,adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of thelung and squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer (including metastatic breast cancer), colon cancer, rectalcancer, colorectal cancer, endometrial or uterine carcinoma, salivarygland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma,testicular cancer, esophageal cancer, tumors of the biliary tract, aswell as head and neck cancer.

In certain embodiments, the cancer is brain, lung, colon, epidermoid,squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, uterine, rectal,oesophageal, testicular, gynecological, thyroid cancer, melanoma,hematologic malignancies such as acute myelogenous leukemia, multiplemyeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma,Kaposi's sarcoma, or any other type of solid or liquid tumors. In someembodiments, the cancer is metastatic cancer. In some embodiments, thecancer is colorectal cancer. In some embodiments, the cancer is coloncancer.

In various embodiments, compounds of formula (I), and related formulaeexhibit a IC50 for the binding to IRAK of less than about 5 μM,preferably less than about 1 μM and even more preferably less than about0.100 μM.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to inhibit IRAK activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing IRAK-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of IRAK activity if expedient.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by IRAK activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byIRAK activity. In certain embodiments, the invention provides the use ofa compound according to formula I or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of a IRAK-mediated disorder.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order toboost the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used to reducethe likelihood of developing a disorder or even prevent the initiationof disorders associated with IRAK activity in advance or to treat thearising and continuing symptoms.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously incurred disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with IRAK activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustinet^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malatei^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinib¹, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab,trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab, elotuzumab,epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab,obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab,siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab,dalotuzumab^(1,2,3), onartuzumab^(1,3), racotumomab, tabalumab^(1,3),EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane I123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide,inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox,technetium (99mTc) arcitumomabt^(1,3), vintafolidet^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴.(¹Prop. INN (Proposed International Nonproprietary Name); ²Rec. INN(Recommended International Nonproprietary Names); ³USAN (United StatesAdopted Name); ⁴no INN).

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

In certain embodiments, a therapeutically effective amount of a compoundof the formula (I), and related formulae and of the other activeingredient depends on a number of factors, including, for example, theage and weight of the animal, the precise disease condition whichrequires treatment, and its severity, the nature of the formulation andthe method of administration, and is ultimately determined by thetreating doctor or vet. However, an effective amount of a compound isgenerally in the range from 0.1 to 100 mg/kg of body weight of therecipient (mammal) per day and particularly typically in the range from1 to 10 mg/kg of body weight per day. Thus, the actual amount per dayfor an adult mammal weighing 70 kg is usually between 70 and 700 mg,where this amount can be administered as an individual dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound per se.

In certain embodiments, the pharmaceutical formulations can beadministered in the form of dosage units, which comprise a predeterminedamount of active ingredient per dosage unit. Such a unit can comprise,for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularlypreferably 5 mg to 100 mg, of a compound according to the invention,depending on the disease condition treated, the method of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations can be administered in the form of dosage units whichcomprise a predetermined amount of active ingredient per dosage unit.Preferred dosage unit formulations are those which comprise a daily doseor part-dose, as indicated above, or a corresponding fraction thereof ofan active ingredient. Furthermore, pharmaceutical formulations of thistype can be prepared using a process, which is generally known in thepharmaceutical art.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting IRAK activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting IRAK, or a mutant thereof, activity in a biological sample ina positive manner, comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

The compounds of the invention are useful in-vitro as unique tools forunderstanding the biological role of IRAK, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of IRAK and the interaction of IRAK. The present compoundsare also useful in the development of other compounds that interact withIRAK since the present compounds provide important structure-activityrelationship (SAR) information that facilitate that development.Compounds of the present invention that bind to IRAK can be used asreagents for detecting IRAK in living cells, fixed cells, in biologicalfluids, in tissue homogenates, in purified, natural biologicalmaterials, etc. For example, by labeling such compounds, one canidentify cells expressing IRAK. In addition, based on their ability tobind IRAK, compounds of the present invention can be used in in-situstaining, FACS (fluorescence-activated cell sorting), sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA(enzyme-linked immunoadsorptive assay), etc., enzyme purification, or inpurifying cells expressing IRAK inside permeabilized cells. Thecompounds of the invention can also be utilized as commercial researchreagents for various medical research and diagnostic uses. Such uses caninclude but are not limited to: use as a calibration standard forquantifying the activities of candidate IRAK inhibitors in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of IRAK ligands, thecompounds can be used to block recovery of the presently claimed IRAKcompounds; use in the co-crystallization with IRAK enzyme, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to IRAK, enabling the determination ofenzyme/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein IRAK is preferably activated or suchactivation is conveniently calibrated against a known quantity of anIRAK inhibitor, etc.; use in assays as probes for determining theexpression of IRAK in cells; and developing assays for detectingcompounds which bind to the same site as the IRAK binding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat IRAK-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or in animal. The orally bioavailable and active new chemicalentities of the invention improve convenience for patients andcompliance for physicians.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of IRAK, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

The symbols and conventions used in the following descriptions ofprocesses, schemes, and examples are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society or the Journal of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade).

All reactions were conducted at room temperature unless otherwise noted.All compounds of the present invention were synthesiszed by processesdeveloped by the inventors. ¹H-NMR spectra were acquired on a BrukerAvance III 400 or a Bruker DPX-300 MHz. Chemical shifts are expressed inparts per million (ppm, δ units). Coupling constants are in units ofhertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), qt (quintuplet) or br (broad).

Mass spectra were obtained on Agilent 1200 Series mass spectrometersfrom Agilent Technologies, using either Atmospheric Chemical Ionization(APCI) or Electrospray Ionization (ESI). Column: XBridge C8, 3.5 μm,4.6×50 mm; Solvent A: water+0.1% TFA; Solvent B: ACN+0.1% TFA; Flow: 2ml/min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min:5% B, 10 min 5% B or a LC/MS Waters ZMD (ESI).

HPLC data were obtained using Agilent 1100 series HPLC from Agilenttechnologies using a column (XBridge C8, 3.5 μm, 4.6×50 mm) and twomobile phases (mobile phase A: water+0.1% TFA; mobile phase B: ACN+0.1%TFA). The flow rate was 2 ml/min. The gradient method was: 0 min: 5% B;8 min: 100% B; 8.1 min: 100% B; 8.5 min: 5% B; 10 min 5% B, unlessotherwise indicated.

The microwave reactions were conducted using Biotage Initiator MicrowaveSynthesizer or a single mode microwave reactor Emrys™ Optimiser usingstandard protocols that are known in the art.

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

The following abbreviations refer to the abbreviations used below:

Ac (acetyl), BINAP (2,2′-bis(disphenylphosphino)-1,1′-binaphthalene),dba (dibenzylidene acetone), Bu (Butyl), tBu (tert-Butyl), DCE(dichloroethane), DCM (Dichloromethane), δ (chemical shift), DIEA(di-isopropyl ethylamine), DMA (dimethyl acetamide), DMSO (DimethylSulfoxide), DMF (N,N-Dimethylformamide), Dppf (1,1-bis (diphenylphosphine ferrocene)), EtOAc (Ethyl acetate), EtOH (Ethanol), eq(equivalent), g (gram), cHex (Cyclohexane), HATU(N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminiumhexafluorophosphate), HPLC (High Performance Liquid Chromatography), h (hour), LDA(lithium diisopropyl amine), LiHMDS (lithium bis(trimethylsilyl)amide),MHz (Megahertz), MeOH (Methanol), min (minute), mL (milliliter), mmol(millimole), mM (millimolar), mp (melting point), MS (MassSpectrometry), MW (microwave), NMR (Nuclear Magnetic Resonance), O/N(overnight), PBS (Phosphate Buffered Saline), RT (room temperature), TEA(Triethyl amine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), TLC(Thin Layer Chromatography).

In general, the compounds according to Formula (I) and related formulaeof this invention can be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those of ordinary skilled inthe art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by the personskilled in the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, N.Y., 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

Intermediate 1: tert-butyl4-{4-[6-(3-aminophenyl)pyridin-3-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

A mixture of 5-bromo-2-iodopyridine (500 mg; 1.76 mmol; 1.00 eq.),3-aminophenylboronic acid (241 mg; 1.76 mmol; 1.00 eq.), potassiumcarbonate (974 mg; 7.04 mmol; 4.00 eq.) and Pd(PPh₃)₄ (102 mg; 0.09mmol; 0.05 eq.) in dioxane (7.50 mL) and water (3.75 mL) was heated in asealed vial at 100° C. overnight. The reaction mixture was then dilutedwith EtOAc and washed with water. The organic layer was back-extractedwith EtOAc and the combined organic layers were dried over MgSO₄,filtered and concentrated to give 3-(5-bromopyridin-2-yl)aniline (438mg, 100%). 3-(5-bromopyridin-2-yl)aniline (435 mg; 1.75 mmol; 1.00 eq.),4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester (659 mg; 1.75 mmol; 1.00 eq.), potassium carbonate(965 mg; 6.98 mmol; 4.00 eq.) and Pd(PPh₃)₄ (101 mg; 0.09 mmol; 0.05eq.) were then suspended in dioxane (6.5 mL) and water (3.4 mL) in asealed vial. The reaction mixture was heated in the MW at 120° C. for 30minutes, then diluted with EtOAc and washed with water. The organiclayer was back-extracted with EtOAc. The combined organic layers weredried over MgSO₄, filtered and concentrated. Purification by flashchromatography on silica (EtOAc:DCM, gradient from 50 to 100%) affordedthe title compound as a beige solid (390 mg; 37%). 1H NMR (300 MHz,DMSO-d6): 8.87 (dd, J=2.0 Hz, 0.6 Hz, 1H), 8.42 (s, 1H), 8.02-7.98 (m,2H), 7.79 (dd, J=8.4 Hz, 0.6 Hz, 1H), 7.34 (t, J=2.0 Hz, 1H), 7.19 (dt,J=7.8 Hz, 1.5 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.62-6.58 (m, 1H), 5.18(s, 2H), 4.43-4.34 (m, 1H), 4.07-3.99 (m, 2H), 2.93 (m, 2H), 2.07-2.03(m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H).

Intermediate 2: tert-butyl4-{4-[6-(3-iodophenyl)pyridin-3-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Isopentyl nitrite (stabilized, 375 μl; 2.79 mmol; 3.00 eq.) was added toa solution of tert-butyl4-4-[6-(3-aminophenyl)pyridin-3-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate(390 mg; 0.93 mmol; 1.00 eq.), Copper(I) iodide (212 mg; 1.12 mmol; 1.20eq.) and diiodomethane (377 μl; 4.65 mmol; 5.00 eq.) in dry THF (15.6mL) and the reaction mixture was refluxed for 1 hour. The reactionmixture was then filtered through a celite pad and the filtrate wasconcentrated to dryness. Purification by flash chromatography on silica(EtOAc: Heptane, gradient from 20 to 100% of EtOAc) afforded the titlecompound (215 mg; 43.6%). 1H NMR (300 MHz, DMSO-d6): 8.94 (dd, J=2.0 Hz,0.7 Hz, 1H), 8.47-8.45 (m, 2H), 8.13-7.95 (m, 4H), 7.79-7.76 (m, 2H),7.29 (t, J=7.8 Hz, 1H), 4.45-4.35 (m, 1H), 4.08-4.00 (m, 2H), 2.94 (m,2H), 2.04-2.03 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H). LC/MS: 531.5(M+1).

Intermediate 3:4-[4-(6-Amino-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic AcidTert-Butyl Ester

A mixture of 5-Iodo-pyridin-2-ylamine (1.10 g; 5.00 mmol; 1.0 eq.),4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester (2.07 g; 5.50 mmol; 1.10 eq.), Pd(PPh₃)₄ (289 mg;0.25 mmol; 0.05 eq.) and potassium carbonate (2.07 g; 15.00 mmol; 3.00eq.) in dioxane (38 mL) was heated in a sealed vial at 100° c.overnight. The reaction mixture was then diluted with EtOAc and washedwith water. The organic layer was back-extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered andconcentrated. The solid obtained was suspended in EtOAc, filtered anddried under vacuum to give the title compound as a beige solid (1 g,70%). HPLC: (254 nm) 95%; Rt (min) 2.60; LC/MS: 344.3 (M+1).

Intermediate 4:4-[4-(6-Iodo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic AcidTert-Butyl Ester

The title compound was obtained following procedure described forintermediate 2 from4-[4-(6-Amino-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acidtert-butyl ester (1.21 g; 3.52 mmol; 1.00 éq.) as a brown gum (390 mg;0.86 mmol). HPLC: (254 nm) 68%; Rt (min) 4.44. LC/MS: 455.4 (M+1).

Intermediate 5:4-[4-(6′-Chloro-[2,2′]bipyridinyl-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forexample 1, step 1 from4-[4-(6-Iodo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acidtert-butyl ester (150 mg; 0.33 mmol; 1.00 eq.) and2-Chloro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (87mg; 0.36 mmol; 1.10 eq.) as a brown gum (180 mg, quantitative). LC/MS:440.4 (M+1).

Intermediate 6:3-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicAcid Tert-Butyl Ester

5-Bromo-2,4-dichloro-pyrimidine (2.12 g; 9.33 mmol; 2.00 eq.) was addedto a suspension of NaH (134 mg; 5.6 mmol; 1.20 eq.) in THF (16 mL)maintained at 0° C. The reaction mixture was stirred for 5 min beforethe addition of 3-Aminomethyl-piperidine-1-carboxylic acid tert-butylester (1.0 g; 4.67 mmol; 1.00 eq.). It was then stirred at 0° C.overnight, diluted with methanol, filtered through a celite pad andconcentrated. Purification by flash chromatography on silica(EtOAc:Hexane, gradient from 0 to 100% then MeOH:DCM, gradient from 0 to20%) afforded the title compound in the second eluting fraction as awhite powder (587 mg, 31%). 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s,1H), 4.84 (brs, 1H), 4.37-4.12 (m, 2H), 3.25-3.09 (m, 2H), 3.03 (m, 1H),2.99-2.86 (m, 1H), 1.90 (m, 2H), 1.81 (m, 1H), 1.67 (m, 1H), 1.46 (s,9H), 1.32 (m, 1H). LC/MS: 405.0 (M+1).

Intermediate 7:3-{[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicAcid Tert-Butyl Ester

A mixture of3-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (252 mg; 0.62 mmol; 1.00 eq.),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(194 mg; 0.93 mmol; 1.50 eq.), K₃PO₄ (264 mg; 1.24 mmol; 2.00 eq.) andPd(dppf)Cl₂ (23 mg; 0.03 mmol; 0.05 eq.) in water (0.2 mL) and2-Methyltetrahydrofuran (5.6 mL) was degassed with Ar and heated in asealed tube to 100° C. for 2 h. It was then filtered through a celitepad and concentrated under reduced pressure. Purification by flashchromatography on silica (EtOAc:Hexanes, gradient from 0 to 100%)afforded the title compound as a white solid (97 mg, 38%). LC/MS: 407.7(M+1).

Intermediate 8:[1-(5-Bromo-2-chloro-pyrimidin-4-yl)-piperidin-3-ylmethyl]-carbamic AcidTert-Butyl Ester

The title compound was obtained following procedure described forintermediate 6 from 5-Bromo-2,4-dichloro-pyrimidine (3.3 mL; 23.33 mmol;2.00 eq.) and piperidin-3-ylmethyl-carbamic acid tert-butyl ester (2.5g; 11.7 mmol; 1.00 eq.) as a yellow solid (4 g, 80%). 1H NMR (400 MHz,Chloroform-d) δ 8.24 (s, 1H), 4.81 (s, 1H), 4.27 (t, J=13.7 Hz, 2H),3.16 (m, 2H), 3.10-3.02 (m, 1H), 3.02-2.85 (m, 1H), 1.98-1.86 (m, 2H),1.81 (m, 1H), 1.74-1.61 (m, 1H), 1.48 (s, 9H), 1.42-1.23 (m, 1H). LC/MS:405.1 (M+1).

Intermediate 9:{1-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidin-3-ylmethyl}-carbamicAcid Tert-Butyl Ester

A mixture of[1-(5-Bromo-2-chloro-pyrimidin-4-yl)-piperidin-3-ylmethyl]-carbamic acidtert-butyl ester (750 mg; 1.85 mmol; 1.00 eq.),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(462 mg; 2.22 mmol; 1.20 eq.), potassium phosphate (785 mg; 3.70 mmol;2.00 eq.) and Pd(dppf)Cl₂.DCM (135 mg; 0.18 mmol; 0.10 eq.) in water(0.60 mL), and 2-Methyltetrahydrofuran (5.6 mL) was degassed with Ar andheated in a sealed tube to 100° C. for 2 h. It was then filtered througha celite pad and concentrated under reduced pressure. Purification byflash chromatography on silica (EtOAc:Hexanes, gradient from 0 to 100%)afforded the title compound as a yellow foam (640 mg, 85%). ¹H NMR (400MHz, Chloroform-d) δ 7.94 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 4.85 (t,J=6.4 Hz, 1H), 3.96 (s, 3H), 3.87-3.73 (m, 1H), 3.73-3.58 (m, 1H), 3.04(dt, J=12.8, 5.8 Hz, 1H), 2.87 (m, 3H), 1.86-1.68 (m, 2H), 1.68-1.54 (m,1H), 1.43 (brs, 11H); LC/MS: 407.2 (M+1).

Intermediate 10:4-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forintermediate 6 from 5-Bromo-2,4-dichloro-pyrimidine (1.33 mL; 9.33 mmol;2.00 eq.) and 4-Aminomethyl-piperidine-1-carboxylic acid tert-butylester (1 g; 4.67 mmol; 1.00 eq.) as a white solid (1.6 g, 83%). LC/MS:405 (M+1).

Intermediate 11:4-{[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forintermediate 9 from3-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (300 mg; 0.74 mmol; 1.00 eq.) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(prepared as described in WO 2014008992; 231 mg; 1.11 mmol; 1.50 eq) as(125 mg, 42%). LS/MS: 407.2 (M+1).

Intermediate 12:5-Bromo-2-chloro-4-(tetrahydro-pyran-2-ylmethoxy)-pyrimidine

5-Bromo-2,4-dichloro-pyrimidine (4.16 mL; 29.3 mmol; 2.00 eq.) was addedto a suspension of NaH (702 mg; 17.6 mmol; 1.20 eq.) in THF (37 mL)maintained at 0° C. The reaction mixture was stirred for 5 min beforethe addition of (tetrahydro-pyran-2-yl)-methanol (1.7 mL; 14.6 mmol;1.00 eq.). It was then stirred at 0° C. overnight, diluted withmethanol, filtered through a celite pad and concentrated. Purificationby flash chromatography on silica (EtOAc: Hexane, 0 to 50%) afforded thetitle compound as a white solid (1.61 g, 34%). LC/MS: 307.0 (M+H).

Intermediate 13:5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-(tetrahydro-pyran-2-ylmethoxy)-pyrimidine

A solution of5-Bromo-2-chloro-4-(tetrahydro-pyran-2-ylmethoxy)-pyrimidine (400 mg;1.30 mmol; 1.00 eq.),1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(406 mg; 1.95 mmol; 1.50 eq.), K₃PO₄ (552 mg; 2.60 mmol; 2.00 eq.) andPd(dppf)Cl2*DCM (95 mg; 0.13 mmol; 0.10 eq.) in water (0.30 mL) and2-Methyltetrahydrofuran (3.00 mL; 29.95 mmol; 23.03 eq.) was degassed bybubbling 15 min with Ar(g), then heated to 100° C. for 30 min. It wasthen cooled to room temperature and filtered through a celite pad. Thepad was rinsed with EtOAc and the filtrate was concentrated underreduced pressure. Purification by flash chromatography on silica (EtOAc:Hexane, gradient from 0 to 100% then MeOH/DCM, gradient from 10 to 20%)afforded the title compound as a light yellow solid (272 mg, 64.4%).LC/MS: 309.9 (M+1).

Intermediate 14:5-Bromo-2-chloro-4-(3-methyl-oxetan-3-ylmethoxy)-pyrimidine

(3-Methyl-oxetan-3-yl)-methanol (2 g; 19.6 mmol; 1.00 eq.) was addeddropwise over 15 min to a suspension of Sodium hydride (60% in oil, 0.98g; 24.48 mmol; 1.25 eq.) and 5-Bromo-2,4-dichloro-pyrimidine (8.92 g;39.2 mmol; 2.00 eq.) in THF (50 mL) maintained at 0° C. under nitrogenatmosphere. The solvent was then removed under reduced pressure and thecrude residue was purified by flash column chromatography on silica(EtOAc: Hexane, gradient from 0 to 100% then MeOH: DCM gradient from 10to 20%) to afford the title compound as a white solid (375 mg, 6.5%). 1HNMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 4.63 (d, J=6.1 Hz, 2H), 4.55(s, 2H), 4.47 (d, J=6.1 Hz, 2H), 1.46 (s, 3H).

Intermediate 15

The title compound was prepared following procedure described forintermediate 13 from5-Bromo-2-chloro-4-(3-methyl-oxetan-3-ylmethoxy)-pyrimidine (375 mg;1.28 mmol; 1.00 eq.),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(399 mg; 1.92 mmol; 1.50 eq.) as a tan solid (165.1 mg, 44%). LC/MS:407.72 (M+1).

Intermediate 16:3-{[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forintermediate 9 from3-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (400 mg; 0.99 mmol; 1.00 eq.) and1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(308 mg; 1.48 mmol; 1.50 eq.) as a brown solid (680 mg, quantitative).LC/MS: 407.2 (M+1).

Intermediate 17: 5-Bromo-2-chloro-4-(oxetan-3-ylmethoxy)-pyrimidine

The title compound was obtained following the procedure described forIntermediate 14 from 5-Bromo-2,4-dichloro-pyrimidine (1.62 mL; 11.35mmol; 2.00 eq.) and oxetan-3-yl-methanol (500 mg; 5.68 mmol; 1.00 eq.)as a yellow oil (500 mg, 31.5%). 1H NMR (400 MHz, Chloroform-d) δ 8.42(d, J=1.1 Hz, 1H), 4.84 (ddd, J=7.7, 6.3, 1.1 Hz, 2H), 4.67 (dd, J=6.7,1.1 Hz, 2H), 4.62-4.42 (m, 2H), 3.48 (qt, J=5.8 Hz, 1H).

Intermediate 18:2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-ylmethoxy)-pyrimidine

The title compound was obtained following the procedure described forintermediate 9 from 5-Bromo-2-chloro-4-(oxetan-3-ylmethoxy)-pyrimidine(500 mg; 1.79 mmol; 1.00 eq.) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(558 mg; 2.68 mmol; 1.50 eq.) as a white solid (109 mg, 22%). LC/MS:281.1 (M+1).

Intermediate 19:4-{[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forintermediate 9 from4-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (800 mg; 1.97 mmol; 1.00 eq.),1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(615 mg; 2.96 mmol; 1.50 eq.) as a brown solid (541 mg, 67%). LC/MS:407.2 (M+1).

Intermediate 20:[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(tetrahydro-pyran-4-ylmethyl)-amine

The title compound was obtained following procedure described forintermediate 7 from(5-Bromo-2-chloro-pyrimidin-4-yl)-(tetrahydro-pyran-4-ylmethyl)-amine(335 mg; 1.09 mmol; 1.00 eq.) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(341 mg; 1.64 mmol; 1.50 eq.) as a brown oil (206 mg, 49%). LC/MS: 308.2(M+1).

Intermediate 21:(5-Bromo-2-chloro-pyrimidin-4-yl)-(1-methanesulfonyl-piperidin-4-yl)-amine

A solution of 5-Bromo-2,4-dichloro-pyrimidine (1.72 mL; 13.46 mmol; 1.20eq.), 1-Methanesulfonyl-piperidin-4-ylamine (2.0 g; 11.22 mmol; 1.00eq.) and DIPEA (3.0 mL; 17.22 mmol; 1.54 eq.) in THF (34.00 mL) wasstirred at RT for 90 min under nitrogen atmosphere. Solvent was removedunder reduced pressure and the crude was purified by flashchromatography on silica (EtOAc: hexane, gradient from 60% to 100%) togive the title compound as a white solid (318 mg, 8%). LC/MS: 369.0(M+1).

Intermediate 22:[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine

The title compound was obtained following the procedure described forintermediate 7 from(5-Bromo-2-chloro-pyrimidin-4-yl)-(1-methanesulfonyl-piperidin-4-yl)-amine(2165 mg; 5.86 mmol; 1.00 eq.) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(1828 mg; 8.78 mmol; 1.50 eq.) as a beige solid (870 mg, 32%). LC/MS:371.1 (M+1).

Intermediate 23: 2-Chloro-4-isopropylamino-pyrimidine-5-carboxylic AcidEthyl Ester

A solution of 2,4-Dichloro-pyrimidine-5-carboxylic acid ethyl ester(8.00 g; 34.4 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (12.10 mL; 68.77mmol; 2.00 eq.) and Isopropylamine (2.09 g; 35.1 mmol; 1.02 eq.) in DCM(80 mL) was stirred for 3 h at RT. The reaction mixture was then washedwith water and organic layer was dried over sodium sulfate, filtered andconcentrated. Purification by flash chromatography on silica affordedthe title compound as a colorless liquid (7.6 g; 30.28 mmol; 88.1%). 1HNMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 4.32-4.27(m, 2H), 4.25-4.22 (m, 1H), 1.30 (t, J=7.0 Hz, 3H), 1.21 (d, J=6.5 Hz,6H); HPLC: (254 nm) 96%; Rt 4.69 min; LC/MS: 244 (M+1).

Intermediate 24:4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicAcid Ethyl Ester

Pd(dppf)₂Cl₂.CH₂Cl₂ was added to a degassed solution of2-Chloro-4-isopropylamino-pyrimidine-5-carboxylic acid ethyl ester (7.0g; 28.0 mmol; 1.00 eq.), potassium carbonate (7.98 g; 56.00 mmol; 2.00eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(11 g; 30.80 mmol; 1.10 eq.) in Dioxane-1,4 (140 mL) and Water (35 mL).The reaction mixture was stirred at 100 OC overnight. It was thenfiltered through a celite pad and concentrated under reduced pressure.The residue was diluted with Water (50 mL) and extracted with ethylacetate (2×50 mL). Combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. Purification by flash chromatographyon silica (EtOAc: PE, 50:50) afforded the title compound as a whitesolid (3.5 g, 29%). HPLC: (254 nm) 90%; Rt 3.88 min; LC/MS: 366.3 (M+1).

Intermediate 25:4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicAcid Hydrazide

Hydrazine monohydrate (0.17 mL; 3.47 mmol; 5.00 eq.) was added to astirred solution of4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicacid ethyl ester (300 mg; 0.69 mmol; 1.00 eq.) in Ethanol (6.00 mL). Thereaction mixture was refluxed at 90° C. overnight. It was then cooleddown to room temperature and concentrated under reduced pressure (halfvolume). The precipitated was filtered and washed with cold Ethanol toafford the title compound as a white solid (180 mg, 73%). 1H NMR (400MHz, DMSO): 9.94 (s, 1H), 8.66 (s, 1H), 8.60 (d, J=7.4 Hz, 1H), 8.48 (s,1H), 8.21 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.88 (s, 1H), 7.70 (d, J=7.8Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 4.52 (brs, 2H), 4.47-4.39 (m, 1H), 3.88(s, 3H), 1.28 (d, J=6.52 Hz, 6H). HPLC: (254 nm) 94%; Rt 2.9 min; LC/MS:352.3 (M+1).

Intermediate 26:5-{4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicAcid Ethyl Ester Step 1:(N′-{4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carbonyl}-hydrazino)-oxo-aceticAcid Ethyl Ester

Chloro-oxo-acetic acid ethyl ester (0.32 mL; 2.82 mmol; 1.05 eq.) wasadded drop wise to a solution of4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicacid hydrazide (0.95 g; 2.68 mmol; 1.0 eq.) and TEA (1.05 mL; 8.05 mmol;3.00 eq.) in DCM (28.50 mL) maintained at 0° C. The reaction mixture wasallowed to warm to RT and stirred for 30 min. It was quenched with asaturated solution of NaHCO₃, then extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated.Purification by flash chromatography on silica (DCM:MeOH) afforded thetitle compound as a yellow solid (1 g, 70%). HPLC: (254 nm) 92%; Rt 3.36min; LC/MS: 452.2 (M+1).

Step 2:5-{4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicAcid Ethyl Ester

A solution of(N′-{4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carbonyl}-hydrazino)-oxo-aceticacid ethyl ester (0.78 g; 1.62 mmol; 1.00 eq.) and2,4-Bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide(1.49 g; 3.57 mmol; 2.20 eq.) in THF (39 mL) was heated at reflux for 3h. The reaction mixture was then diluted with ethyl acetate and washedtwice with 10% NaHCO₃ solution. The organic layer was dried over Na₂SO₄,filtered and concentrated. Purification by flash chromatography onsilica (DCM:MeOH) afforded the title compound as a yellow solid (1 g,82%). 1H NMR (400 MHz, DMSO-d6) δ: 8.99 (s, 1H), 8.85 (d, J=7.24 Hz,1H), 8.55 (s, 1H), 8.31-8.21 (m, 2H), 7.90 (s, 1H), 7.75 (d, J=7.40 Hz,1H), 7.52 (t, J=8.08 Hz, 1H), 5.75 (s, 2H), 4.65-4.60 (m, 1H), 4.49-4.44(m, 2H), 3.89 (s, 3H), 3.80-3.60 (m, 1H), 1.39-1.35 (m, 9H). HPLC: (254nm) 99%; Rt 4.33 min; LC/MS: 450.2 (M+H).

Intermediate 27:4-(1-tert-Butoxycarbonyl-piperidin-3-ylamino)-2-chloro-pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was obtained following the procedure described forIntermediate 23 from 2,4-Dichloro-pyrimidine-5-carboxylic acid ethylester (5.0 g; 21.49 mmol; 1.00 eq.) and 3-Amino-piperidine-1-carboxylicacid tert-butyl ester (4.43 g; 21.92 mmol; 1.02 eq.) as a yellow gum(8.50 g; 17.14 mmol; 79.7%). HPLC: (254 nm) 72%; Rt 5.27 min; LC/MS: 385(M+1).

Intermediate 28:3-{5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester Step 1:4-(1-tert-Butoxycarbonyl-piperidin-3-ylamino)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was obtained following the procedure described forintermediate 24 from4-(1-tert-Butoxycarbonyl-piperidin-3-ylamino)-2-chloro-pyrimidine-5-carboxylicacid ethyl ester (8.0 g; 16.01 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(6.29 g; 17.61 mmol; 1.10 eq.) as a gum (5.0 g, 59%). HPLC: (254 nm)93%; Rt 4.51 min; LC/MS: 507.2 (M+1).

Step 2:3-{5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described inintermediate 25 from4-(1-tert-Butoxycarbonyl-piperidin-3-ylamino)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicacid ethyl ester (3.0 g; 5.68 mmol; 1.00 eq.) as an off-white solid (2g, 69%).

HPLC: (254 nm) 89%; Rt 3.53 min; LC/MS: 493.2 (M+H).

Intermediate 29:3-{5-(5-Ethoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2-[3-(1-methyl-H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester Step 1:3-{5-(N′-Ethoxyoxalyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forintermediate 26, step 1 from3-{5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (500 mg; 0.98 mmol; 1.00 eq.) in DCM (10 mL) andChloro-oxo-acetic acid ethyl ester (0.12 mL; 1.03 mmol; 1.05 eq.) as ayellow solid (420 mg, 66%). HLPC: (254 nm) 89%; Rt 3.94 min; LC/MS:593.3 (M+H).

Step 2:3-{5-(5-Ethoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forintermediate 26, step 2 from3-{5-(N′-Ethoxyoxalyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (300 mg; 0.47 mmol; 1.00 eq.) as a yellow solid(150 mg, 52%). HPLC: (254 nm) 88%; Rt 5.05 min; LC/MS: 591.2 (M+H).

Intermediate 30:4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-chloro-pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was obtained following the procedure described forintermediate 23 from 2,4-Dichloro-pyrimidine-5-carboxylic acid ethylester (2.50 g; 10.74 mmol; 1.00 eq.) and3-Aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (2.06 g;10.96 mmol; 1.02 eq.) as a colorless gum (2.0 g, 54%). HPLC: (254 nm)98%; Rt 6.35 min; LC/MS: 369.0 (M+H).

Intermediate 31:3-({5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-azetidine-1-carboxylicAcid Tert-Butyl Ester Step 1:4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was obtained following the procedure described forintermediate 24 from4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-chloro-pyrimidine-5-carboxylicacid ethyl ester (2.20 g; 5.81 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(2.28 g; 6.40 mmol; 1.10 eq.) as a white solid (2.0 g, 54%). 1H NMR (400MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.51-8.47 (m, 1H), 8.21-8.19 (m, 2H),7.89 (d, J=0.44 Hz, 1H), 7.75-7.72 (m, 1H), 7.49 (t, J=7.76 Hz, 1H),4.36-4.30 (m, 2H), 3.88 (s, 6H), 3.74-3.80 (m, 2H), 3.20-3.00 (m, 1H),1.35-1.31 (m, 12H). HPLC (XBridge C8 (50×4.6 mm, 3.5 μm): (254 nm) 96%;Rt 4.0 min; LC/MS: 493.2 (M+H).

Step 2:3-({5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-azetidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forintermediate 25 from phenyl]-pyrimidine-5-carboxylic acid ethyl ester(1.10 g; 2.14 mmol; 1.00 eq.) as an off-white solid (900 mg, 82%). HPLC(254 nm) 90%; Rt 3.43 min; LC/MS: 479.2 (M+H).

Intermediate 32:5-{4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicAcid Methyl Ester Step 1:3-({5-(N′-Methoxyoxalyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-azetidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forintermediate 26, step 1 from3-({5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester (400 mg; 0.78 mmol; 1.00 eq.) andChloro-oxo-acetic acid methyl ester (0.08 mL; 0.82 mmol; 1.05 eq.) as ayellow solid (300 mg, 66%) HPLC: (254 nm) 94%; Rt 3.55 min; LC/MS: 565.3(M+H).

Step 2:5-{4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicAcid Methyl Ester

The title compound was obtained following the procedure described forintermediate 26, step 2 from3-({5-(N′-Methoxyoxalyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester (300 mg; 0.51 mmol; 1.00 eq.) as a yellow solid(150 mg; 52%). HPLC: (254 nm) 92%; Rt 4.44 min; LC/MS: 563.3 (M+H).

Intermediate 33:[5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanoneStep 1: 6-Chloro-4-isopropylamino-nicotinic Acid Hydrazide

A solution of Hydrazine hydrate monohydrate (8.07 mL; 164 mmol) and6-Chloro-4-isopropylamino-nicotinic acid ethyl ester (7.0 g; 27.4 mmol)in Ethanol (50 mL) was reflux at 80° C. for 3 hrs. The reaction mixturewas then concentrated under reduced pressure and the crude wastriturated with diethyl ether to afford the desired product as whitesolid (6 g, 79%). LC/MS: 229.00 (M+1).

Step 2:[N′-(6-Chloro-4-isopropylamino-pyridine-3-carbonyl)-hydrazino]-oxo-aceticAcid Methyl Ester

The title compound was obtained following the procedure described forIntermediate 26, step 1 from 6-Chloro-4-isopropylamino-nicotinic acidhydrazide (5.5 g; 21.6 mmol) as a white solid (4 g, 50%). 1H NMR (400MHz, DMSO-d6): δ 10.44 (s, 1H), 8.56 (s, 1H), 8.40 (s, 1H), 6.70 (s,1H), 3.82 (s, 3H), 3.48-0.00 (m, 1H), 1.16-1.09 (m, 6H).

Step 3:5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazole-2-carboxylicAcid Methyl Ester

The title compound was obtained following the procedure described forintermediate 26, step 2 from[N′-(6-Chloro-4-isopropylamino-pyridine-3-carbonyl)-hydrazino]-oxo-aceticacid methyl ester (4.0 g; 10.8 mmol) as an off white solid (3 g, 67%).LC/MS: 313.0 (M+1).

Step 4:[5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone

A solution of5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazole-2-carboxylicacid methyl ester (2.5 g; 7.2 mmol) and (R)-Pyrrolidin-3-ol (3.84 g;43.16 mmol) in Methanol (25 mL) was heated in microwave at 80° C. for 1hrs. Solvent was removed under reduced pressure and the crude waspurified by flash chromatography on silica (PE, EtOAc) to afford thetitle compound as a pale yellow solid (1 g, 41%). 1H NMR (400 MHz,DMSO-d6) δ 8.76 (d, 1H), 8.55 (s, 1H), 6.95 (s, 1H), 5.08 (d, 1H), 4.39(d, 1H), 4.19-3.93 (m, 3H), 3.68-3.53 (m, 2H), 1.99 (m, 2H), 1.27 (d,6H).

Intermediate 33:2-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-acetamide

A mixture of 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-acetamide (AuroraBuilding Blocks; 200 mg; 0.75 mmol; 1.00 eq.),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-1H-pyrazole (166 mg;0.79 mmol; 1.05 eq.), Tetrakis(triphenylphosphine)palladium (4.35 mg;0.002 mmol; 0.01 eq.), potassium carbonate (125 mg; 0.90 mmol; 1.20 eq.)in dioxane (6 mL) and water (0.6 mL) was stirred in a sealed vial at 90°C. overnight. The reaction mixture was then concentrated under reducedpressure and purified by flash chromatography on KPNH (EtOAc: MeOHgradient from 0:100 to 30:70) to give the title compound as a whitesolid (183 mg, 87%). LC/MS: 267.1 (M+H).

Intermediate 34:[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-yl]-cyclobutyl-amine

A mixture of (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclobutyl-amine (AuroraBuilding Blocks, 200 mg; 0.76 mmol; 1.00 eq.),1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(166 mg; 0.80 mmol; 1.05 eq.), Bis(triphenylphosphine)palladium (II)dichloride (2.81 mg; 0.002 mmol; 0.01 eq.) and potassium carbonate (126mg; 0.91 mmol; 1.20 eq.) dioxane (6 mL) and Water (0.60 mL) was stirredat 90° C. overnight in a sealed vial. The reaction mixture was thenconcentrated under reduced pressure and purified by flash chromatographyon silica (EtOAc: hexane, gradient from 10 to 50%) to give the titlecompound as a white solid (63 mg, 30%). LC/MS: 264.6 (M+H)

Intermediate 35:6-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-2-aza-spiro[3.3]heptane-2-carboxylicAcid Tert-Butyl Ester

A mixture of 5-Bromo-2,4-dichloro-pyrimidine (650 mg; 2.85 mmol; 1.00eq.), 6-Amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester(727 mg; 3.42 mmol; 1.20 eq.), Ethyl-diisopropyl-amine (1.49 mL; 8.56mmol; 3.00 eq.) in NMP (5.0 mL) was stirred at 50° C. overnight. Themixture was then concentrated under reduced pressure and purified byflash chromatography on silica (EtOAc: Hexanes, gradient from 0 to 40%)to give the title compound as a white solid (1.2 g, 100%). LC/MS: 403(M+H) 403.

Intermediate 36:6-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylicAcid Tert-Butyl Ester

A mixture of6-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (200 mg; 0.50 mmol; 1.00 eq.),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(155 mg; 0.74 mmol; 1.50 eq.), Bis(triphenylphosphine)palladium (II)dichloride (1.83 mg; 0.002 mmol; 0.01 eq.) and potassium carbonate (82mg; 0.59 mmol; 1.20 eq.) in dioxane (5 mL) and water (0.5 mL) wasstirred at 100° C. overnight in a sealed vial. The mixture was thenconcentrated under reduced pressure and purified by flash chromatographyon silica (EtOAc:Hexanes, gradient from 20 to 100% then MeOH: EtOAc,gradient from 0 to 20%) to give the title compound as a yellow solid(201 mg, 95%). LC/MS: 405.2 (M+H).

Intermediate 37:4-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicAcid Tert-Butyl Ester

4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.39 g;15.80 mmol; 1.20 eq.) and 5-Bromo-2,4-dichloro-pyrimidine (3.00 g; 13.17mmol; 1.00 eq.) were dissolved in THF (30 mL) and DIPEA (6.9 mL). Themixture was stirred under N2 at 50° C. for 2 h. The reaction mixture wasthen diluted with water (150 mL) and EtOAc (75 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated to afford a colorless oil.Purification by flash chromatography on silica (EtOAc:Hexane, gradientfrom 10 to 30%) afforded the title compound as a white solid (4.0 g,75%). ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.75 (t, 1H), 3.92 (d,2H), 3.27 (t, 2H), 2.79-2.59 (bs, 2H), 1.81 (m, 1H), 1.60 (dd, 2H), 1.40(s, 9H), 1.02 (qd, 2H). LC/MS: 349 ((M-tBu)+H).

Intermediate 38: tert-butylN-[(1S,2S,3S)-3-amino-2-hydroxycyclohexyl]-N-methylcarbamate (RelativeStereochemistry-Racemic) Step 1: benzylN-[(1S,2R,3S)-2-hydroxy-3-(methylamino)cyclohexyl]carbamate (RelativeStereochemistry-Racemic)

A solution of benzylN-[(1S,2S,6R)-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (relativestereochemistrty, racemic, prepared as described in Org. Lett., 2003, p.4955-49557, 730 mg, 2.66 mmol, 1.00 eq.) and methyl amine (850 mg, 26.82mmol, 10.1 eq.,) in Methanol (10 mL) was stirred in a sealed tube for 16h at 45° C. The resulting mixture was concentrated under vacuum andpurified by flash chromatography on silica (methanol/DCM, 1:10) toafford the tittle compound as a light yellow oil (800 mg, 97%).

Step 2: benzylN-[(1S,2S,3S)-3-{[(tert-butoxy)carbonyl](methyl)amino}-2-hydroxycyclohexyl]carbamate(Relative Stereochemistry-Racemic)

A solution of benzylN-[(1S,2R,3S)-2-hydroxy-3-(methylamino)cyclohexyl]carbamate (Racemic,800 mg, 2.59 mmol, 1.00 eq.), TEA (535 mg, 5.18 mmol, 2.00 eq.,), Boc2O(864 mg, 3.88 mmol, 1.50 eq.) in DCM (40 mL) was stirred for 2 h at 25°C. The resulting mixture was concentrated under vacuum and purified byflash chromatography on silica (methanol/DCM, 1:15) to afford the tittlecompound a light yellow solid (1 g, 92%).

Step 3: tert-butylN-[(1S,2S,3S)-3-amino-2-hydroxycyclohexyl]-N-methylcarbamate (RelativeStereochemistry-Racemic)

Pd/C (253 mg, 0.24 mmol, 0.10 eq.) was added to a solution of benzylN-[(1S,2S,3S)-3-[[(tert-butoxy)carbonyl](methyl)amino]-2-hydroxycyclohexyl]carbamate(1 g, 2.38 mmol, 1.00 eq.) in MeOH (4 mL) maintained under nitrogenatmosphere. The mixture was then hydrogenated at room temperature for 16hours using a hydrogen balloon. The solids were filtered out and theresulting mixture was concentrated under vacuum to afford the tittlecompound as a light yellow solid (630 mg, 98%).

Intermediate 39: tert-butylN-[(1S,2S,3S)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-hydroxycyclohexyl]-N-methylcarbamate(Relative Stereochemistry-Racemic)

A solution of tert-butylN-[(1S,2S,3S)-3-amino-2-hydroxycyclohexyl]-N-methylcarbamate (630 mg,2.32 mmol, 1.00 eq.), 5-bromo-2,4-dichloropyrimidine (652 mg, 2.80 mmol,1.21 eq.) and DIEA (612 mg, 4.64 mmol, 2.00 eq.) in THF (10 mL) wasstirred at RT for 2 h. The resulting mixture was concentrated undervacuum and purified by flash chromatography on silica (EtOAc/PE, 1:2) toafford the title compound as a yellow solid (630 mg, 56%). LC/MS(Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min;Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; 254 nm): (purity)90%; [M+H]+ Cac. 435.1; found 435.1.

Intermediate 40: tert-butylN-[(1S,2S,3S)-3-{[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino}-2-hydroxycyclohexyl]-N-methylcarbamate(Relative Stereochemistry-Racemic)

A mixture of tert-butylN-[(1S,2S,3S)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-hydroxycyclohexyl]-N-methylcarbamate(630 mg, 1.30 mmol, 1.00 eq., 90%),1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (415 mg,1.95 mmol, 1.50 eq., 98%), Pd(dppf)Cl₂.CH₂Cl₂ (108 mg, 0.13 mmol, 0.10eq., 98%) and K3PO4 (566 mg, 2.61 mmol, 2.01 eq.) in dioxane (10 mL) andwater (2 mL) was degassed with nitrogen and heated at 100° C. for 2 h ina sealed tubed. The resulting mixture was concentrated under vacuum andpurified by flash chromatography on silica (EtOAc/PE, 1:1) to afford thetittle compound as a yellow solid (420 mg, 66%).

Intermediate 41: tert-butylN-[1-(5-bromo-2-chloropyrimidin-4-yl)-5,5-difluoropiperidin-3-yl]carbamate

The title compound was obtained following the procedure described forintermediate 39 from tert-butyl N-(5,5-difluoropiperidin-3-yl)carbamate(500 mg, 2.01 mmol, 0.93 eq.) as a white solid (460 mg, 37%).

Intermediate 42: tert-butylN-{1-[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-5,5-difluoropiperidin-3-yl}carbamate

The title compound was obtained following the procedure described forintermediate 40 from tert-butylN-[1-(5-bromo-2-chloropyrimidin-4-yl)-5,5-difluoropiperidin-3-yl]carbamate(460 mg, 0.81 mmol, 1.00 eq.) as a white solid (220 mg, 57%). LC/MS(Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min;Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; 254 nm): (purity)90%; [M+H]+ Cac. 428.2; found 428.2.

Intermediate 43: (1S,2S,6S)-2-amino-6-fluorocyclohexan-1-ol (RelativeStereochemistry, Racemic) Step 1: BenzylN-[(1S,2S,6R)-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (RelativeStereochemistry, Racemic)

A solution of benzyl N-(cyclohex-2-en-1-yl)carbamate (400 mg, 1.56 mmol,1.00 eq., 90%), sodium bicarbonate (267 mg, 3.11 mmol, 2.00 eq., 98%),and m-CPBA (549 mg, 3.12 mmol, 2.00 eq., 98%) in DCM (25 mL) was stirredfor 3 h at 20° C. The reaction was then quenched by the addition of 15mL of Na₂SO₃ and diluted with 30 mL of water. It was then extracted withDCM (3×15 mL). Combined organic layers were concentrated under vacuumand purified by flash chromatography on silica (EA/PE, 1:5) to give thetitle compound as a brown solid.

Step 2: benzyl N-[(1S,2S,3S)-3-fluoro-2-hydroxycyclohexyl]carbamateCarbamate (Relative Stereochemistry, Racemic)

HF-pyridine (0.5 mL, 3.88 mmol, 1.52 eq., 70% purity) was added dropwiseto a solution of DCM (10 mL) maintained under nitrogen atmosphere at 0°C. A solution of the of benzylN-[7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (700 mg, 2.55 mmol, 1.00eq.) in dichloromethane (3 mL) was then added dropwise and the resultingmixture was stirred for 2 h at 0° C. The pH value of the solution wasadjusted to 7 with saturated sodium bicarbonate (aq.). After dilutionwith 20 mL of H₂O, The resulting mixture was extracted with DCM (3×15mL). Combined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. Purification by flashchromatography on silica (EA/PE, 1:15 to 1:4) afforded the titlecompound as a light yellow solid (700 mg, 93% yield).

Step 3: (1S,2S,6S)-2-amino-6-fluorocyclohexan-1-ol (RelativeStereochemistry, Racemic)

The title compound was obtained following the procedure described forexample 38, step 3 from benzylN-[(1S,2S,3S)-3-fluoro-2-hydroxycyclohexyl]carbamate (racemic, relativeconfiguration, 700 mg, 2.36 mmol) as a white solid (300 mg, 86%).

Intermediate 44:(1S,2S,6S)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-6-fluorocyclohexan-1-ol(Relative Stereochemistry, Racemic)

The title compound was obtained following the procedure described forexample 39 from (1S,2S,6S)-2-amino-6-fluorocyclohexan-1-ol (Intermediate43, 300 mg, 2.03 mmol, 1.00 eq.) as a yellow solid (500 mg, 68%). LC/MS(Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min;Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; 254 nm): (purity)90%; [M+H]+ Cac. 324.0; found 324.0.

Intermediate 45:(1S,2S,6S)-2-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-6-fluorocyclohexan-1-ol(Relative Stereochemistry, Racemic)

The title compound was obtained following the procedure described forexample 40 from(1S,2S,6S)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-6-fluorocyclohexan-1-ol(Intermediate 44, racemic, 440 mg, 1.22 mmol, 1.00 eq.) a yellow solid(360 mg, 82%). LC/MS (Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um;Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flowrate: 1.0 mL/min; Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; 254nm): [M+H]+ Cac. 326.0; found 326.0.

Intermediate 46: (1S,6R)-6-amino-2,2-difluorocyclohexan-1-ol Step 1:2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexan-1-ol

A solution of (1R)-1-phenylethan-1-amine (2.375 g, 18.62 mmol, 1.30 eq.,95%) in DCM (12 mL) was cooled to 0° C. and treated withtrimethylaluminium (11 mL, 1.20 eq., 2M in toluene) under nitrogenatmosphere. It was stirred for 1 h before the addition of a solution of(1R,6R)-2,2-difluoro-7-oxabicyclo[4.1.0]heptane (racemic, relativestereochemistry, 2.260 g, 14.32 mmol, 1.00 eq.) in DCM (50 mL). Theresulting solution was stirred for 2 days at RT. The reaction was thenquenched by the addition of NH₄Cl aq. The aqueous layer was extractedwith dichloromethane and the combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtrated and concentratedunder vacuum. Purification by flash chromatography on silica(MTBE/petroleum ether, 1:10) afforded the title compound (first elutingisomer) as a white solid (1.36 g, 33%).

Step 2: (1S,6R)-6-amino-2,2-difluorocyclohexan-1-ol

A solution of(1S,6R)-2,2-difluoro-6-[[(1R)-1-phenylethyl]amino]cyclohexan-1-ol (1.360g, 4.79 mmol, 1.00 eq.) in MeOH (30 mL) was degassed with nitrogenbefore the addition of Palladium on carbon (1.701 g, 9.59 mmol, 2.00eq., 60%). The reaction mixture was then placed under Hydrogenatmosphere (1 atm.) and stirred O/N at RT. The mixture was filteredthrough a celite pad and concentrated to afford the title compound as awhite solid (765 mg, 95%). 1H NMR (300 MHz, Methanol-d4, ppm) 3.40-3.30(m, 1H), 2.73 (m, 1H), 2.05 (m, 1H), 1.90-1.39 (m, 4H), 1.34-1.17 (m,1H).

Intermediate 47:(1S,6R)-6-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2,2-difluorocyclohexan-1-ol

The title compound was obtained following the procedure described forintermediate 39 from (1S,6R)-6-amino-2,2-difluorocyclohexan-1-ol (200mg, 1.19 mmol, 1.00 eq.) as a yellow solid (451 mg, 87%).

Intermediate 48:(1S,6R)-6-{[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino}-2,2-difluorocyclohexan-1-ol

The title compound was obtained following the procedure described forintermediate 40 from(1S,6R)-6-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2,2-difluorocyclohexan-1-ol(451 mg, 1.04 mmol, 1.00 eq.) as a yellow solid (208 mg, 58%).

Intermediate 49:(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-amineHydrochloride (Racemic—Relative Stereochemistry) Step 1:2,2,2-trichloro-N-[(1S,2S,3R)-2,3-dihydroxvcycloheptyl]acetamide(Racemic—Relative Stereochemistry)

A solution of2,2,2-trichloro-N-[(1S,2S,3R)-2,3-dihydroxycycloheptyl]acetamide(racemic—relative stereochemistry, prepared as described in JOC, 2002, p7946-7956, 10 mg, 0.03 mmol, 1.00 eq.), 2,2-dimethoxypropane (7 mg, 0.06mmol, 2.06 eq.) and TsOH (0.5 mg, 0.09 eq.) in Acetone (1 mL) wasstirred at RT for 16 h. The reaction mixture was then concentrated underreduced pressure and the residue was redissolved in DCM. The organiclayer was washed with sat. NaHCO₃, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford the title compound whichwas used directly in the next step.

Step 2:(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-amineHydrochloride (Racemic—Relative Stereochemistry)

NaBH₄ (71 mg, 1.78 mmol, 5.04 eq.) was added portionwise to a solutionofN-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-2,2,2-trichloroacetamide(racemic, 130 mg, 0.35 mmol, 1.00 eq.) in ethanol (10 mL) maintained at0° C. The resulting solution was then stirred for 16 h at 40° C. Thereaction was quenched by the addition of a solution of hydrogen chloride(1M). The mixture was finally concentrated under reduced pressure toafford the title compound as a white solid (140 mg).

Intermediate 50:N-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-5-bromo-2-chloropyrimidin-4-amine(Racemic—Relative Stereochemistry)

The title compound was obtained following the procedure described forintermediate 39 from(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-aminehydrochloride (racemic, 185 mg, 0.90 mmol, 0.79 eq.) as an off-whitesolid (210 mg, 44%). 1H NMR (300 MHz, Chloroform-d) 8.11 (s, 1H), 6.01(d, J=8.2 Hz, 1H), 4.49 (t, J=7.3 Hz, 1H), 4.34 (d, J=8.3 Hz, 1H), 4.23(t, J=9.1 Hz, 1H), 2.22-1.90 (m, 2H), 1.73 (dd, J=11.4, 5.8 Hz, 3H),1.54 (s, 6H), 1.37 (s, 3H).

Intermediate 51:N-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(Racemic—Relative Stereochemistry)

The title compound was obtained following the procedure described forintermediate 40 fromN-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-5-bromo-2-chloropyrimidin-4-amine(racemic, 240 mg, 0.57 mmol, 1.00 eq.), as an yellow oil (185 mg, 77%).LC/MS (Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min;Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; 254 nm): (purity)87.3%; [M+H]+ Cac. 378.2; found 378.2.

Intermediate 52: (1S,2S,3S)-3-amino-2-(methoxymethoxy)cyclohexyl Acetate(Racemic—Relative Stereochemistry) Step 1:(1S,2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxycyclohexyl Acetate(Racemic—Relative Stereochemistry)

A mixture of benzylN-[(1S,2S,6R)-7-oxabicyclo[4.1.0]heptan-2-yl]carbamate (obtained asdescribed in Org. Lett., 2003, p 4955-4957, 350 mg, 1.27 mmol, 1.00 eq.,NaOAc (214 mg, 2.56 mmol, 2.01 eq.) and acetic acid (5 mL) was stirredfor 30 min at 100° C. The reaction mixture was then cooled to RT anddiluted with 60 mL of water. The pH was adjusted to 7 by addition of asolution of sodium bicarbonate. And the resulting solution was extractedwith DCM (3×). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated under vacuum to affordthe title compound as an off-white solid (300 mg, 69%). LC/MS (Column:Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min; Gradient: 5% B to100% B in 2.2 min, hold 1.0 min; 254 nm): [M+Na]+23 Cac. 330.0; found330.0.

Step 2:(1S,2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-(methoxymethoxy)cyclohexylAcetate (Racemic—Relative Stereochemistry)

A solution of(1S,2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxycyclohexyl acetate(250 mg, 0.73 mmol, 1.00 eq.), DIEA (194 mg, 1.47 mmol, 2.01 eq.) andchloro(methoxy)methane (91 mg, 1.11 mmol, 1.51 eq.) in DMF (15 mL) wasstirred for 3 h at 70° C. under nitrogen atmosphere. The reaction wasthen quenched by the addition of a sat. Na₂CO₃ solution. It was thenextracted with DCM (3×). Combined organic layers were washed with brine,dried over magnesium sulfate, filtered and concentrated. Purification byflash chromatography on silica (EtOAc/PE, 1:6) afforded the titlecompound as a yellow solid (270 mg, 94%). LC/MS: [M+H]+ Cac. 352.1;found 352.1.

Step 3: (1S,2S,3S)-3-amino-2-(methoxymethoxy)cyclohexyl Acetate(Racemic—Relative Stereochemistry)

The title compound was obtained following the procedure described forintermediate 43, step 2 from(1S,2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-(methoxymethoxy)cyclohexylacetate (250 mg, 0.64 mmol, 1.00 eq.) as a colorless oil (150 mg, 97%).LC/MS: [M+H]+ Calc. 218.2; found 218.2.

Intermediate 53:(1S,2S,3S)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-(methoxymethoxy)cyclohexylAcetate (Relative Stereochemistry, Racemic)

The title compound was obtained following the procedure described forexample 39 from (1S,2S,3S)-3-amino-2-(methoxymethoxy)cyclohexyl Acetate(Intermediate 52, racemic, 370 mg, 1.53 mmol, 1.00 eq.), as a yellowsolid (560 mg, 80%). MS: m/z=408.1 [M+H]⁺.

Intermediate 54:(1S,2S,3S)-3-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-2-(methoxymethoxy)cyclohexylAcetate ((Relative Stereochemistry, Racemic)

The title compound was obtained following the procedure described forexample 40 from(1S,2S,3S)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-(methoxymethoxy)cyclohexylacetate (Intermediate 53, racemic, 560 mg, 1.23 mmol, 1.00 eq.) as ayellow solid (330 mg, 59%).

Intermediate 55:5-bromo-2-chloro-N-(cyclohept-2-en-1-yl)pyrimidin-4-amine

The title compound was obtained following the procedure described forintermediate 39 from cyclohept-2-en-1-amine (650 mg, 2.92 mmol, 1.02eq.) as a yellow oil (460 mg, 48%). LC/MS: [M+H]+ Calc. 302.0; found302.0.

Intermediate 56:2-chloro-N-(cyclohept-2-en-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

The title compound was obtained following the procedure described forintermediate 40 from5-bromo-2-chloro-N-(cyclohept-2-en-1-yl)pyrimidin-4-amine (intermediate55, 450 mg, 1.34 mmol, 1.00 eq.) as a yellow oil (100 mg, 22%). LC/MS:[M+H]+ Calc. 304.1; found 304.0.

Example 1:2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridineHydrochloride Step 1: tert-butyl4-(4-{6-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-4-[6-(3-iodophenyl)pyridin-3-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate(215 mg; 0.41 mmol; 1.00 eq.),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (84mg; 0.41 mmol; 1.00 eq.), Pd(PPh₃)₄ (23 mg; 0.02 mmol; 0.05 eq.) andpotassium carbonate (168 mg; 1.22 mmol; 3.0 eq.) in dioxane (3.2 mL) andwater (1.61 mL) was heated in a sealed tube in MW at 120° C. for 30minutes. The reaction mixture was then diluted with EtOAc and washedwith water. The organic layer was back-extracted with EtOAc and thecombined organic layers were dried over MgSO4, filtered andconcentrated. Purification by flash chromatography on silica (EtOAct:Heptanes, gradient from 50 to 100%) afforded the title compound as ayellow gum (110 mg; 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.94 (dd, J=2.0Hz, 1.0 Hz, 1H), 8.46 (s, 1H), 8.26-8.05 (m, 2H), 8.07-8.05 (m, 3H),7.96 (d, J=1.0 Hz, 1H), 7.93 (ddd, J=7.9 Hz, 2.0 Hz, 1.0 Hz, 1H), 7.61(ddd, J=7.9 Hz, 2.0 Hz, 1.0 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 4.46-4.35(m, 1H), 4.09 (m, 2H), 3.89 (s, 3H), 2.94 (m, 2H), 2.09-2.04 (m, 2H),1.89-1.75 (m, 2H), 1.43 (s, 9H). LC/MS: 485.6 (M+1).

Step 2:2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridineHydrochloride

A solution of tert-butyl4-(4-6-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyridin-3-yl-1H-pyrazol-1-yl)piperidine-1-carboxylate(110 mg; 0.23 mmol; 1.00 eq.) and hydrogen chloride (0.85 mL of a 4Nsolution in dioxane; 3.40 mmol; 15 eq.) in DCM (1.1 mL) and MeOH (1.10mL) was stirred at RT for 1 hour. The reaction mixture was filtered offand the resulting solid was washed with DCM. Purification byautopreparative LC/MS afforded the title compound as a yellow powder (65mg; 67%). 1H NMR (300 MHz, DMSO-d6) δ 9.35-9.26 (m, 1H), 9.13-9.06 (m,1H), 9.05 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.36(t, J=2.0 Hz, 1H), 8.32-8.29 (m, 2H), 8.26 (s, 1H), 8.03 (d, J=1.0 Hz,1H), 7.96-7.92 (m, 1H), 7.73 (dt, J=7.8 Hz, 1.0 Hz, 1H), 7.55 (t, J=7.8Hz, 1H), 4.61-4.51 (m, 1H), 3.90 (s, 3H), 3.42-3.38 (m, 2H), 3.16-3.06(m, 2H), 2.29-2.14 (m, 4H); HPLC: (254 nm) 100%; Rt (min) 2.02. LC/MS:385.5 (M+1).

Example 2:6′-(1-Methyl-1H-pyrazol-4-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′]bipyridinylStep 1:4-{4-[6′-(1-Methyl-1H-pyrazol-4-yl)-[2,2′]bipyridinyl-5-yl]-pyrazol-1-yl}-piperidine-1-carboxylicAcid Tert-Butyl Ester

A mixture of4-[4-(6′-Chloro-[2,2′]bipyridinyl-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester (130 mg; 0.30 mmol; 1.0 eq.), Pd(PPh₃)₂Cl₂ (21 mg;0.03 mmol; 0.10 eq.), PPh₃ (15.5 mg; 0.06 mmol; 0.20 eq.), cesiumfluoride (134.7 mg; 0.89 mmol; 3.00 eq.) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(92 mg; 0.44 mmol; 1.50 eq.) in 1,2-Dimethoxy-ethane (2.2 mL) was heatedin a sealed vial at 100° C. overnight. The mixture was then filteredthrough a celite pad. Aqueous phase was extracted with DCM and combinedorganic phases were washed with water, dried over MgSO₄, filtered andconcentrated. Purification by flash chromatography on silica (EtOAc:Heptanes, 80:20) afforded the title compound (104 mg, 72%). LC/MS: 486.3(M+1).

Step 2:6′-(1-Methyl-1H-pyrazol-4-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′]bipyridinyl

The title compound was obtained following procedure described forexample 1, step 2 from4-{4-[6′-(1-Methyl-1H-pyrazol-4-yl)-[2,2′]bipyridinyl-5-yl]-pyrazol-1-yl}-piperidine-1-carboxylicacid tert-butyl ester (100 mg; 0.21 mmol; 1.00 eq.) as a beige solid (10mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (d, J=1.7 Hz, 1H), 8.52 (d,J=8.0 Hz, 1H), 8.46-8.43 (m, 2H), 8.32 (bs, 1H), 8.17-8.10 (m, 4H), 7.89(t, J=8.0 Hz, 1H), 7.67 (dd, J=8.0 Hz, 1.0 Hz, 1H), 4.41-4.28 (m, 1H),3.92 (s, 3H), 3.23-3.19 (m, 2H), 2.86-2.73 (m, 2H), 2.13-1.89 (m, 4H).HPLC: (254 nm) 98%; Rt (min) 1.61. LC/MS: 386.4 (M+1).

Example 3:3-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

A mixture of3-{[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (94 mg; 0.23 mmol; 1.00 eq.), Pd(PPh₃)Cl₂ (3.2 mg;0.01 mmol; 0.02 eq.), potassium carbonate (0.15 mL of a 2 M aq.solution),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(prepared as described in WO 2014008992; 79 mg; 0.28 mmol; 1.20 eq.) indegassed dioxane (1.1 mL) was heated in a sealed vial in MW at 150° C.for 20 min. It was then filtered through a celite pad and concentratedunder reduced pressure. Purification by flash chromatography on silica(EtOAc:Hexanes, gradient from 0 to 100% then MeOH:DCM, gradient from 0to 20%) to afford the title compound as a yellow foam (48 mg, 34%). 1HNMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.33 (s, 1H), 8.27 (d, J=7.8Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.64-7.53 (app m,2H), 7.47 (d, J=7.6 Hz, 1H), 4.56 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H),3.86 (d, J=12.3 Hz, 1H), 3.04 (t, J=6.5 Hz, 2H), 2.94-2.80 (t, 1H), 2.72(t, J=11.5 Hz, 1H), 1.95-1.76 (app m, 3H), 1.71 (d, J=12.9 Hz, 1H),1.64-1.50 (m, 1H), 1.44 (s, 9H), 1.23 (td, J=13.9, 13.4, 8.0 Hz, 1H);HPLC: (254 nm) 95.8%; RT (min) 3.629; LC/MS: 429.4 (M+1).

Example 4:{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylmethyl-amineHydrochloride

A solution of3-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (34 mg; 0.06 mmol; 1.0 eq.) and hydrogen chloride(1.0 mL of a 2M solution in Et₂O; 0.2 mmol; 3.3 eq.) in methanol (3.00mL) was stirred at RT for 30 min. The reaction mixture was co-evaporatedwith 5×10 mL Et₂O and dried under reduced pressure to give the titlecompound as a white solid (26 mg, 81%). 1H NMR (400 MHz, Methanol-d4) δ8.61 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H),8.09 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.74 (t, J=7.7 Hz,1H), 4.74 (m, 1H), 4.28 (brs, 1H), 4.15 (s, 3H), 4.05 (s, 3H), 3.21 (d,J=10.5 Hz, 2H), 3.07-2.83 (m, 2H), 2.19 (brs, 1H), 2.05 (d, J=12.6 Hz,1H), 1.84 (d, J=13.2 Hz, 1H), 1.68 (m, 1H), 1.50 (m, 1H). HPLC: (254 nm)100%; RT (min) 2.29. LCMS: 429.2 (M+1).

Example 5:(1-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylmethyl)-carbamicAcid Tert-Butyl Ester

A mixture of{1-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidin-3-ylmethyl}-carbamicacid tert-butyl ester (285 mg; 0.70 mmol; 1.00 eq.), Pd(PPh₃)Cl₂ (98 mg;0.14 mmol; 0.20 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(prepared as described in WO 2014008992; 238 mg, 0.84 mmol, 1.2 eq.) andpotassium carbonate (0.2 mL of a 2M solution in water) in degasseddioxane (3.3 mL) was heated in a sealed vial in 150° C. for 80 min. Itwas then filtered through a celite pad and concentrated under reducedpressure. Purification by flash chromatography on silica (EtOAc:Hexanes,gradient from 0:100% then MeOH:DCM gradient from 0 to 20%), followed bya second purification by Preparative HPLC afforded the title compound asa white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.35 (s,1H), 8.29 (d, J=7.8 Hz, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.72 (d, J=3.3Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H),4.56 (brs, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.94 (d, J=3.0 Hz, 2H), 3.06(t, J=6.5 Hz, 2H), 2.94-2.85 (t, 2H), 2.74 (t, J=11.7 Hz, 1H), 2.35 (t,J=7.3 Hz, 1H), 1.87 (d, J=11.5 Hz, 2H), 1.46 (s, 9H), 1.00 (t, J=7.6 Hz,1H). HPLC: (254 nm) 97.9%; RT (min) 3.48; LC/MS: 529.3 (M+1).

Example 6:C-(1-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-yl)-methylamineHydrochoride

The title compound was obtained following the procedure described forexample 4 from(1-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylmethyl)-carbamicacid tert-butyl ester (78 mg; 0.15 mmol; 1.00 eq.) as a yellow powder(30 mg, 30%). 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.21 (s,1H), 8.17 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 8.05 (s, 1H), 8.00 (s, 1H),7.95 (d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.68 (t, J=7.8 Hz, 1H), 4.73 (brs,1H), 4.25 (brs, 1H), 4.15 (s, 3H), 4.05 (s, 3H), 3.23 (m, 2H), 3.08-2.84(m, 2H), 2.21 (m, 1H), 2.05 (brs, 1H), 1.84 (brs, 1H), 1.68 (brs, 1H),1.51 (brs, 1H), 1.32 (m, 1H). HPLC: (254 nm) 94.6%; RT (min) 2.231;LC/MS: 429.3 (M+1). HPLC: (254 nm) 94.6%; RT (min) 2.23; LC/MS: 429.3(M+1).

Example 7:{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-4-ylmethyl-amineStep 1:4-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forexample 3 from4-{[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (125 mg; 0.31 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(105 mg; 0.37 mmol; 1.20 eq.) as a yellow foam (87 mg, 48%). LC/MS:529.4 (M+1).

Step 2:{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-4-ylmethyl-amineHydrochloride

A solution of4-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (84 mg; 0.16 mmol; 1.00 eq.) and hydrogen chloride(3.0 mL of a 2M solution in Et₂O; 0.16 mmol; 1.00 eq.) in MeOH (3.00 mL)was stirred at RT for 30 min. The reaction mixture was co-evaporatedwith 5×10 mL Et₂O and dried under reduced pressure to give the titlecompound as a yellow oil (68 mg, quantitative). 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H),8.13 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.78 (s,1H), 7.68 (d, J=7.8 Hz, 1H), 4.77-4.54 (m, 1H), 4.06 (s, 3H), 4.01 (s,3H), 3.21 (t, J=12.6 Hz, 2H), 2.91 (d, J=6.9 Hz, 2H), 2.19-2.00 (m, 1H),2.00-1.84 (m, 2H), 1.57-1.37 (m, 2H); HPLC: (254 nm) 98.3%; RT (min)2.21; LC/MS: 429.3 (M+1).

Example 8:5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-(tetrahydro-pyran-2-ylmethoxy)-pyrimidine

The title compound was obtained following the procedure described forexample 3 from2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-4-(tetrahydro-pyran-2-ylmethoxy)-pyrimidine(209 mg; 0.68 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(prepared as described in WO 2014008992; 231 mg; 0.81 mmol; 1.20 eq.) asa beige powder (38 mg, 12%). 1H NMR (400 MHz, Chloroform-d) δ 9.23 (s,1H), 8.58 (d, J=1.9 Hz, 1H), 8.33 (dt, J=7.7, 1.4 Hz, 1H), 7.88 (s, 1H),7.75 (s, 1H), 7.59 (dt, J=7.7, 1.5 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.45(s, 1H), 6.94 (d, J=2.2 Hz, 1H), 4.64 (d, J=5.2 Hz, 2H), 4.00 (s, 3H),3.99 (s, 3H), 3.88 (m, 1H), 3.61-3.47 (m, 2H), 1.87-1.76 (m, 2H),1.64-1.52 (m, 4H); UPLC: (254 nm) 93%; RT (min) 3.9; LC/MS: 431.2 (M+1).

Example 9:4-(3-Methyl-oxetan-3-ylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine

The title compound was obtained following the procedure described forexample 3 from2-Chloro-4-(3-methyl-oxetan-3-ylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidine(151 mg; 0.51 mmol; 1.00 eq.), and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(prepared as described in WO 2014008992; 175 mg; 0.62 mmol; 1.20 eq.) asa white solid (165 mg, 44%). 1H NMR (400 MHz, Methanol-d4) δ 8.87 (s,1H), 8.55 (d, J=1.9 Hz, 1H), 8.31 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.09(s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48 (t,J=7.7 Hz, 1H), 4.83 (d, J=6.1 Hz, 2H), 4.70 (s, 2H), 4.59 (d, J=6.0 Hz,2H), 3.96 (s, 3H), 3.95 (s, 3H), 1.51 (s, 3H); UPLC: (254 nm) 100%; RT(min) 3.27; LC/MS: 417.2 (M+1).

Example 10:{5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylmethyl-amineStep 1:3-({5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forexample 3 from3-{[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (261 mg; 0.64 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(219 mg; 0.77 mmol; 1.20 eq.) as beige solid (19 mg, 55%). LC/MS: 529.4(M+1).

Step 2:{5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylmethyl-aminehydrochloride

The title compound was obtained following procedure described forexample 4 from3-({5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (15 mg; 0.03 mmol; 1.00 eq.) as a white solid (10mg, 80%). 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.47-8.40 (m,1H), 8.18 (s, 1H), 8.13 (d, J=7.7 Hz, 1H), 8.01 (s, 1H), 7.95 (d, J=7.8Hz, 1H), 7.87-7.81 (m, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.08-6.99 (m, 1H),4.08 (s, 3H), 4.05 (s, 3H), 3.61-3.48 (d, 2H), 2.96 (q, J=13.5, 12.4 Hz,2H), 2.42 (brs, 2H), 2.08 (dd, J=25.8, 14.3 Hz, 2H), 1.84 (t, J=13.1 Hz,2H), 1.64-1.42 (m, 2H), 1.20 (s, 1H); HPLC: (254 nm) 100%; RT (min)2.462. LC/MS: calc.: 429.2 (M+1).

Example 11:5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-(oxetan-3-ylmethoxy)-pyrimidine

The title compound was obtained following the procedure described forexample 3 from2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-ylmethoxy)-pyrimidine(55 mg; 0.20 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(67 mg; 0.24 mmol; 1.20 eq.) as a white solid (13 mg, 16%). 1H NMR (400MHz, Chloroform-d) δ 8.83 (s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.30 (d,J=7.8 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H),7.60 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 5.06-4.96 (m, 2H), 4.88(d, J=5.6 Hz, 2H), 4.75 (t, J=6.0 Hz, 2H), 3.99 (s, 6H), 3.59 (qt, J=5.5Hz, 1H); UPLC (H2O TFA 0.1%-ACN TFA 0.1%; Gradient 8 min TFA): (254 nm)80%; RT (min) 2.97; LC/MS: 403.2 (M+1).

Example 12:{5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-4-ylmethyl-amineStep 1:4-({5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following procedure described forexample 3 from4-{[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (541 mg; 1.33 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(453 mg; 1.60 mmol; 1.20 eq.) as a beige solid (53 mg, 7%). LC/MS: 529.3(M+1).

Step 2:{5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-4-ylmethyl-amine

The title compound was obtained following procedure described forexample 4 from4-({5-(1-Methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (52 mg; 0.10 mmol; 1.00 eq) as a beige solid (40mg, 94%). 1H NMR (400 MHz, Methanol-d4) δ 8.69 (d, J=0.9 Hz, 1H), 8.41(d, J=2.2 Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.00 (s, 1H),7.95 (d, J=7.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H),7.04 (d, J=2.4 Hz, 1H), 4.08 (s, 3H), 4.00 (d, J=3.2 Hz, 3H), 3.52-3.44(m, 2H), 3.12-3.00 (m, 2H), 2.35-2.21 (m, 1H), 2.14 (d, J=14.4 Hz, 2H),1.75-1.54 (m, 2H), 1.20 (t, J=7.0 Hz, 2H); UPLC: (254 nm) 100%; RT (min)1.9; LC/MS: 429.3 (M+1).

Example 13:{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-(tetrahydro-pyran-4-ylmethyl)-amine

The title compound was obtained following procedure described forexample 3 from[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(tetrahydro-pyran-4-ylmethyl)-amine(206 mg; 0.67 mmol; 1.00 eq.) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(228 mg; 0.80 mmol; 1.20 eq.) as a beige solid (93 mg, 32%). 1H NMR (400MHz, Chloroform-d) δ 8.54-8.49 (m, 1H), 8.25 (m, 2H), 7.88 (s, 1H), 7.75(s, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 5.39(t, J=6.1 Hz, 1H), 5.12 (brs, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.58 (t,J=6.4 Hz, 2H), 3.42 (t, J=11.8 Hz, 2H), 2.00 (m, 1H), 1.77-1.65 (m, 2H),1.46 (m, 2H); UPLC (H2O TFA 0.1%-ACN TFA 0.1%; Gradient 8 min TFA): (254nm) 100%; RT (min) 2.39; LC/MS: 430.2 (M+1).

Example 14:(1-Methanesulfonyl-piperidin-4-yl)-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-amine

The title compound was obtained following the procedure described forexample 3 from[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine(870 mg; 2.35 mmol; 1.00 eq) and1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(780 mg; 2.82 mmol; 1.20 eq.) as a white solid (600 mg, 52%). 1H NMR(400 MHz, Chloroform-d) δ 8.51 (brs, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.21(dd, J=7.8, 1.5 Hz, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.60(dd, J=7.8, 1.6 Hz, 1H), 7.56 (s, 1H), 7.49 (t, J=7.7 Hz, 1H), 5.09 (d,J=7.2 Hz, 1H), 4.36 (m, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.88 (d,J=11.9, 2H), 3.06-2.91 (m, 2H), 2.87 (s, 3H), 2.29 (m, 2H), 1.67 (m,2H); UPLC (H2O TFA 0.1%-ACN TFA 0.1%; Gradient 8 min TFA): (254 nm)100%; RT (min) 2.17; LC/MS: 493.2 (M+1).

Example 15:Isopropyl-[2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-yl]-amineStep 1:4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicAcid N′-acetyl-hydrazide

Acetyl chloride (0.04 mL; 0.53 mmol; 1.05 eq.) was added dropwise to asolution of4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicacid hydrazide (180 mg; 0.50 mmol; 1.00 eq.) and TEA (0.2 mL, 1.51 mmol;3.00 eq.) in DCM (4.5 mL) maintained at 0° C. The reaction mixture waswarmed up to room temperature and stirred for 30 min. It was thenquenched with a saturated NaHCO₃ solution and extracted with DCM. Theorganic layer was dried over Na₂SO₄, filtered and concentrated.Purification by flash chromatography on silica (DCM: MeOH) afforded thetitle compound as a yellow gum (160 mg, 74%). 1H NMR (400 MHz, DMSO-d6)δ: 10.44 (s, 1H), 9.88 (s, 1H), 8.79 (s, 1H), 8.50-8.49 (m, 2H), 8.22(s, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J=8.2 Hz, 1H),7.49 (t, J=7.8 Hz, 1H), 4.50-4.42 (m, 1H), 3.88 (s, 3H), 1.93 (s, 3H),1.28 (d, J=6.52 Hz, 6H). HPLC (254 nm) 90%; Rt 2.88 min; LC/MS: 394.2(M+H).

Step 2:Isopropyl-[2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-yl]-amine

A solution of 2,4-Bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane2,4-disulfide (311 mg; 0.75 mmol; 2.00 eq.) and4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine-5-carboxylicacid N′-acetyl-hydrazide (160 mg; 0.37 mmol; 1.00 eq.) in THF (8.0 mL)was heated to reflux for 2 h. It was then diluted with ethyl acetate andwashed with a 10% NaHCO₃ solution. The organic layer was separated,dried over Na₂SO₄, filtered and concentrated. Purification by flashcolumn chromatography on silica (DCM/MeOH) afforded the title compoundas a yellow solid (80 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (d,J=7.2 Hz, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H),7.89 (s, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.62-4.57(m, 1H), 3.89 (s, 3H), 2.80 (s, 3H), 1.37 (d, J=6.48 Hz, 6H). HPLC: (254nm) 94%; Rt 3.58 min. LC/MS: 392.3 (M+H).

Example 16:((R)-3-Hydroxy-pyrrolidin-1-yl)-(5-{4-isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazol-2-yl)-methanone

Bis(trimethyl aluminium)-1,4-diaza bicyclo(2.2.2)octane adduct (78 mg;0.30 mmol; 1.00 eq.) at 0° C. followed by (R)-Pyrrolidin-3-ol (32 mg;0.36 mmol; 1.20 eq.) were added to a solution of5-{4-Isopropylamino-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicacid ethyl ester (150 mg; 0.30 mmol; 1.00 eq.) in THF (3.00 mL). Thereaction mixture was heated to reflux for 8 h in a sealed tube. It wasthen cooled down to RT, diluted with ethyl acetate and washed with a 1.5N HCl solution. The organic layer was separated, dried over Na₂SO₄,filtered and concentrated. Purification by flash chromatography onsilica (DCM/MeOH) afforded the title compound as a yellow solid (80 mg,51%). 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (s, 1H), 8.88 (d, J=7.20 Hz,1H), 8.55 (t, J=1.52 Hz, 1H), 8.23 (t, J=7.04 Hz, 2H), 7.90 (d, J=0.56Hz, 1H), 7.74 (d, J=7.84 Hz, 1H), 7.52 (t, J=7.72 Hz, 1H), 5.10 (d,J=3.48 Hz, 1H), 4.66-4.61 (m, 1H), 4.38 (d, J=24.84 Hz, 1H), 4.21 (d,J=8.92 Hz, 2H), 3.89 (s, 3H), 3.72-3.51 (m, 2H), 2.05-1.86 (m, 2H),1.40-1.22 (m, 6H). HPLC: (254 nm) 95%; Rt 3.53 min. LC/MS: 491.2 (M+H).

Example 17:[2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-yl]-piperidin-3-yl-amineHydrochloride Step 1:3-{5-(N′-Acetyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forexample 15, step 1 from3-{5-Hydrazinocarbonyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (600 mg; 1.18 mmol; 1.00 eq.) as a yellow solid(500 mg, 70%). HPLC (Column: XBridge C8, 3.5 μm, 4.6×50 mm): (254 nm)81%; Rt 3.5 min; LC/MS: 535.2 (M+H).

Step 2:3-[2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-ylamino]-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forexample 15, step 2 from3-{5-(N′-Acetyl-hydrazinocarbonyl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (500 mg; 0.83 mmol; 1.00 eq.) as a yellow solid(350 mg; 71.2%). HPLC: (254 nm) 74%; Rt 4.21 min; LC/MS: 533.3 (M+H).

Step 3:[2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-yl]-piperidin-3-yl-amineHydrochloride

A solution of3-[2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(5-methyl-[1,3,4]thiadiazol-2-yl)-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester (100 mg; 0.14 mmol; 1.00 eq.) and hydrogenchloride (1 mL of a 4M solution in dioxane) in dioxane (0.5 mL) wasstirred at RT for 4 h. The reaction mixture was then concentrated underreduced pressure and the precipitate was filtered off, washed withdiethyl ether (20 mL) and dried to afford the title compound as whitesolid (20 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (d, J=7.12 Hz,1H), 8.83 (s, 1H), 8.54 (t, J=1.56 Hz, 1H), 8.26 (d, J=7.92 Hz, 1H),8.22 (s, 1H), 7.91 (s, 1H), 7.74-7.72 (m, 1H), 7.51 (t, J=7.72 Hz, 1H),4.60-4.50 (m, 1H), 3.89 (s, 3H), 2.99-2.93 (m, 1H), 2.90-2.82 (m, 1H),2.81-2.80 (m, 4H), 2.30-2.00 (m, 1H), 1.82-1.73 (m, 3H). HPLC: (254 nm)91%; Rt 2.6 min. LC/MS: 433.3 (M+H).

Example 18:5-[2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-4-(piperidin-3-ylamino)-pyrimidin-5-yl]-[1,3,4]thiadiazole-2-carboxylicAcid Methyl Ester Hydrochloride

A solution of3-{5-(5-Methoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (100 mg; 0.17 mmol; 1.00 eq.) and hydrogenchloride (2 mL of a 4M solution in dioxane) in dioxane (5 mL) wasstirred at RT for 4 h. The reaction mixture was then concentrated underreduced pressure and purified by Preparative HPLC to afford the titlecompound as a yellow solid (45 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ:9.08 (s, 1H), 8.91 (d, J=7.20 Hz, 1H), 8.7-8.8 (brs, 2H), 8.57 (s, 1H),8.31 (d, J=7.88 Hz, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.77 (d, J=7.96 Hz,1H), 7.54 (t, J=7.72 Hz, 1H), 4.71 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H),3.32-3.29 (m, 1H), 3.18-3.16 (m, 1H), 2.98-2.95 (m, 1H), 2.17-2.15 (m,1H), 2.01-1.98 (m, 1H), 1.89-1.84 (m, 2H). HPLC: (254 nm) 98%; Rt 3.01min; LC/MS: 477.2 (M+H).

Example 19:5-{4-[(Azetidin-3-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicAcid Methyl Ester Trifluoroacetate

Trifluoroacetic acid (1.00 mL) was added to a solution of5-{4-[(1-tert-Butoxycarbonyl-azetidin-3-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-[1,3,4]thiadiazole-2-carboxylicacid methyl ester (100 mg; 0.17 mmol; 1.00 eq.) in DCM (5 mL) maintainedat 0° C. The reaction mixture was then allowed to warm to RT and stirredfor 2 h. It was then concentrated under reduced pressure and purified bypreparative HPLC to afford the title compound as a yellow solid (20 mg;20%). 1H NMR (400 MHz, DMSO-d6) δ 9.09 (t, J=5.84 Hz, 1H), 9.03 (s, 1H),8.54 (s, 2H), 8.43 (s, 1H), 8.27 (d, J=8.00 Hz, 1H), 8.23 (s, 1H), 7.93(s, 1H), 7.76 (d, J=8.12 Hz, 1H), 7.53 (t, J=7.76 Hz, 1H), 4.03-3.94 (m,9H), 3.90 (s, 3H), 3.36-3.29 (m, 1H). HPLC: (254 nm) 93%; Rt 2.76 min.LC/MS: 463.3 (M+H).

Example 20:((R)-3-Hydroxy-pyrrolidin-1-yl)-{5-[2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-(piperidin-3-ylamino)-pyrimidin-5-yl]-[1,3,4]thiadiazol-2-yl}-methanoneHydrochloride Step 1:3-{5-[5-((R)-3-Hydroxy-pyrrolidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was obtained following the procedure described forexample 16, step 1 from3-{5-(5-Ethoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (150 mg; 0.24 mmol; 1.00 eq.) and(R)-Pyrrolidin-3-ol (32.22 mg; 0.36 mmol; 1.50 eq.) as a yellow solid(100 mg, 63%). HPLC: (254 nm) 94%; Rt 4.07 min; LC/MS: 632.2 (M+H).

Step 2:((R)-3-Hydroxy-pyrrolidin-1-yl)-{5-[2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-(piperidin-3-ylamino)-pyrimidin-5-yl]-[1,3,4]thiadiazol-2-yl}-methanoneHydrochloride

The title compound was obtained following the procedure described forexample 18, step 1 from3-{5-[5-((R)-3-Hydroxy-pyrrolidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (100 mg; 0.15 mmol; 1.00 eq.) as a yellow solid(20 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.96 (d, J=7.24Hz, 1H), 8.75 (s, 2H), 8.56 (s, 1H), 8.31 (d, J=7.84 Hz, 1H), 8.24 (s,1H), 7.94 (s, 1H), 7.76 (d, J=8.12 Hz, 1H), 7.54 (t, J=7.80 Hz, 1H),4.72 (s, 1H), 4.42-4.36 (m, 1H), 4.22-4.17 (m, 1H), 4.01-3.99 (m, 2H),3.90 (s, 3H), 3.61-3.60 (m, 2H), 3.32-3.29 (m, 1H), 3.19-3.17 (m, 1H),2.97 (s, 1H), 2.17-2.16 (m, 1H), 1.98-1.96 (m, 2H), 1.88-1.84 (m, 2H).HPLC (XBridge C8 (50×4.6) mm, 3.5 μm; A: 10 mM NH₄HCO₃ in H₂O, B:ACN;):(254 nm) 98%; Rt 4.55 min. LC/MS: 532.1 (M+H).

Example 21:((R)-3-Hydroxy-pyrrolidin-1-yl)-(5-{4-isopropylamino-6-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridin-3-yl}-[1,3,4]thiadiazol-2-yl)-methanone

A mixture of1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(250 mg; 0.88 mmol; 1.00 eq.),[5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone(324 mg; 0.88 mmol; 1.00 eq.), K₂CO₃ (365 mg; 2.64 mmol; 3.00 eq.) andtrans-Dichlorobis(tricyclohexylphosphine)palladium(II) (6.49 mg; 0.01mmol; 0.01 eq.) in dioxane (4 mL) and in water (0.4 mL) was degassed andheated at 100° C. for 0.5 hour. Upon completion, the reaction wasfiltered and organic layer was concentrated and purified by flashchromatography on silica with a gradient of 10-100% ethyl acetate inhexanes, affording the title compound as a beige solid (115 mg, 27%). 1HNMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.67 (d, 1H), 8.28-8.21 (m, 2H),7.99-7.92 (m, 2H), 7.65 (d, 1H), 7.48 (t, 1H), 7.36 (s, 1H), 3.94-3.87(m, 3H), 5.75 (s, 1H), 5.07 (d, 1H), 4.39 (d, 1H), 4.24 (m, 2H),4.09-3.97 (m, 2H), 3.73-3.50 (m, 2H), 1.34 (d, 6H). HPLC: (254 nm)96.6%; Rt (min) 3.09. LC/MS: 490.2.

Example 22:((R)-3-Hydroxy-pyrrolidin-1-yl)-{5-[4-isopropylamino-6′-(1-methyl-1H-pyrazol-4-yl)-[2,2′]bipyridinyl-5-yl]-[1,3,4]thiadiazol-2-yl}-methanoneStep 1:[5-(6′-Chloro-4-isopropylamino-[2,2′]bipyridinyl-5-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone

A mixture of2-Chloro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(332.71 mg; 1.39 mmol; 1.00 eq.),[5-(6-Chloro-4-isopropylamino-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone(511.00 mg; 1.39 mmol; 1.00 eq.), a solution of K₂CO₃ (575.94 mg; 4.17mmol; 3.00 eq.) in water (0.4 mL) andtrans-Dichlorobis(tricyclohexylphosphine)palladium(II) (10.25 mg; 0.01mmol; 0.01 eq.) in dioxane (4 mL) was degassed few minutes and heated at100° C. for 0.5 hour. Upon completion, the reaction was filtered andorganic layer was concentrated and purified by flash chromatography onsilica with a gradient of 10-100% ethyl acetate in hexanes, affordingthe title compound (175 mg; 15.8%) as a beige solid.

Step 2:((R)-3-Hydroxy-pyrrolidin-1-yl)-{5-[4-isopropylamino-6′-(1-methyl-1H-pyrazol-4-yl)-[2,2′]bipyridinyl-5-yl]-[1,3,4]thiadiazol-2-yl}-methanone

[5-(6′-Chloro-4-isopropylamino-[2,2′]bipyridinyl-5-yl)-[1,3,4]thiadiazol-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone(85 mg; 0.11 mmol; 1.00 eq.) was dissolved in DMF (4.00 mL; 51.44 mmol;481.41 eq.). Then1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(33.35 mg; 0.16 mmol; 1.50 eq.) was added in one portion followed by asolution of NaHCO₃ (10.77 mg; 0.13 mmol; 1.20 eq.) in water (0.40 mL;22.20 mmol; 207.74 eq.). The reaction was degassed with nitrogen gas andBis(triphenylphosphine)palladium(II) chloride (0.38 mg; 0.00 mmol; 0.01eq.) was added. Reaction mixture was stirred at 80° C. overnight. Thereaction mixture was cooled down to RT and diluted with 200 mL water andextracted with ethyl acetate (3×80 mL). The combined organic phase waswashed with water (2×75 mL) and brine (1×75 mL); dried over Na₂SO₄,filtered and concentrated to a golden oil which was purified bypreparative HPLC to give the title compound as a fluffy yellow solid(32.1 mg, 61.2%). 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.84 (s,2H), 8.42 (s, 3H), 8.26-8.19 (m, 3H), 8.16 (d, 4H), 8.00 (s, 3H),7.98-7.90 (m, 3H), 7.75 (d, 3H), 5.09 (s, 3H), 4.43 (s, 2H), 4.38 (s,2H), 4.22 (d, 6H), 4.06 (t, 5H), 3.99-3.92 (m, 9H), 3.75-3.51 (m, 6H),1.99 (dd, 5H), 1.47-1.36 (m, 17H). HPLC: (254 nm) 100%; Rt (min) 2.25.LC/MS: 491.4.

Example 23:2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-4-trifluoromethyl-pyridineStep 1:5-Chloro-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-trifluoromethyl-pyridine

A mixture of 2-Bromo-5-chloro-4-trifluoromethyl-pyridine (0.23 mL; 1.92mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(573 mg; 2.02 mmol; 1.05 eq.), Tetrakis(triphenylphosphine)palladium (11mg; 0.01 mmol; 0.01 eq.) and potassium carbonate (0.32 g; 2.30 mmol;1.20 eq.) in dioxane (10.00 mL) and water (1 mL) was stirred in a sealedtube at 90° C. overnight. It was then concentrated under reducedpressure and purified by flash chromatography on silica (EtOAc: Hexane,gradient from 10 to 50%) to give the title compound as a yellow solid(285 mg, 42%); LC/MS: 338.1 (M+1).

Step 2:2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-4-trifluoromethyl-pyridine

A mixture of5-Chloro-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-trifluoromethyl-pyridine(40 mg; 0.12 mmol; 1.00 eq.),1-(Tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(35 mg; 0.12 mmol; 1.05 eq.), Tetrakis(triphenylphosphine)palladium(0.68 mg; 0.0006 mmol; 0.01 eq.) and potassium carbonate (0.02 g; 0.14mmol; 1.20 eq.) in Dioxane (1 mL) and Water (0.1 mL) was stirred in asealed vial at 150° C. overnight. It was then concentrated under reducedpressure and purified by flash chromatography on silica (Hexane: EtOAc,gradient from 80:20 to 100:0 then EtOAc: MeOH, 100 to 80%) then bypreparative HPLC to give the title compound as a white solid (35 mg,62%). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.32 (d, J=15.7 Hz, 3H),8.20 (s, 1H), 8.06-7.99 (m, 2H), 7.79 (s, 1H), 7.70 (d, J=7.5 Hz, 1H),7.53 (t, J=7.8 Hz, 1H), 4.53 (td, J=10.2, 5.1 Hz, 1H), 4.00 (dt, J=13.6,2.7 Hz, 2H), 3.91 (d, J=1.4 Hz, 3H), 3.50 (td, J=11.2, 3.8 Hz, 2H), 2.04(dtd, J=12.0, 6.7, 5.2, 2.2 Hz, 4H); HPLC: 99.8% (254 nm); Rt (min)4.45; LC/MS: 454.2 (M+1).

Example 24:4-Methyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-pyridineStep 1:2-Chloro-4-methyl-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-pyridine

A mixture of 5-Bromo-2-chloro-4-methyl-pyridine (200 mg; 0.97 mmol; 1.00eq.),1-(Tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(283 mg; 1.02 mmol; 1.05 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (158 mg; 0.19 mmol; 0.20 eq.), cesiumcarbonate (947 mg; 2.91 mmol; 3.00 eq.) s in dioxane (5.00 mL) and water(0.50 mL) was stirred in a sealed vial at 90° C. overnight. It was thenconcentrated under reduced pressure and purified by flash chromatographyon silica (Hexane: EtOAc, gradient from 80 to 20%) to afford the titlecompound as a yellow solid (170 mg, 63%). LC/MS: 278.1 (M+1).

Step 2:4-Methyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-pyridine

A mixture of2-Chloro-4-methyl-5-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-pyridine(50 mg; 0.18 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(54 mg; 0.19 mmol; 1.05 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.74 mg; 0.0006 mmol; 0.01 eq.), cesiumcarbonate (90 mg; 0.27 mmol; 1.50 eq.) in Dioxane (2 mL) and Water (0.20mL) was stirred in a sealed vial at 120° C. overnight. It was thenconcentrated under reduced pressure and purified by flash chromatographyon KPNH (Hexane:EtOAc, gradient 70 to 20%) then by preparative HPLC togive to title compound as a white solid (15 mg, 21%). 1H NMR (400 MHz,DMSO-d6) δ 8.69 (s, 1H), 8.30-8.21 (m, 4H), 7.99-7.86 (m, 5H), 7.61 (d,J=7.4 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 4.49 (p, J=8.4, 7.6 Hz, 1H),4.04-3.97 (m, 3H), 3.90 (d, J=1.3 Hz, 3H), 3.55-3.46 (m, 3H), 2.04 (td,J=10.6, 9.2, 3.7 Hz, 5H); HPLC: 91% (254 nm); LC/MS: 400.2 (M+1).

Example 25 and 26:2-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-acetamideformate and{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-aceticAcid Formate

A mixture of2-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-acetamide(50 mg; 0.19 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(80 mg; 0.28 mmol; 1.50 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (15mg; 0.02 mmol; 0.10 eq.) and cesium carbonate (91.6 mg; 0.28 mmol; 1.50eq.) in dioxane (2 mL) and water (0.20 mL) was stirred at 120° C.overnight. The reaction mixture was then concentrated under reducedpressure and purified by flash chromatography on KPNH (EtOAc: MeOHgradient from 0 to 100%) to give the title compounds as a mixture. Thetwo compounds were separated by preparative HPLC:

First eluting fraction (example 25,2-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-acetamideformate): white solid (9 mg, 11%): 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d,J=1.9 Hz, 1H), 8.42 (s, OH), 8.28 (s, 1H), 8.23-8.15 (m, 2H), 8.11 (s,1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.53 (s, 1H),7.45 (t, J=7.7 Hz, 1H), 7.12 (s, 1H), 6.93 (t, J=5.4 Hz, 1H), 6.63 (s,1H), 4.03-3.88 (m, 8H); HPLC: 98.8% (254 nm); LC/MS: 389.2 (M+H).

Second eluting fraction (example 26,5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-aceticformate): white solid (12 mg, 14.7%): 1H NMR (400 MHz, DMSO-d6) δ 8.51(s, 1H), 8.30 (s, 1H), 8.20-8.14 (m, 2H), 8.07 (s, 1H), 7.91 (s, 1H),7.78 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.08 (t,J=5.5 Hz, 1H), 6.52 (s, OH), 4.08 (s, 2H), 3.92 (d, J=15.5 Hz, 4H);HPLC: 98.6% (254 nm); LC/MS: 390.2 (M+1)

Example 27:Cyclobutyl-{5-(1-methyl-1H-pyrazol-3-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-amine

A mixture of[2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-yl]-cyclobutyl-amine(60 mg; 0.23 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(97 mg; 0.34 mmol; 1.50 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (18mg; 0.02 mmol; 0.10 eq.) and cesium carbonate (111 mg; 0.34 mmol; 1.50eq.) in dioxane (2.00 mL) and water (0.20 mL) was stirred at 120° C.overnight in a sealed vial. The reaction mixture was then concentratedunder reduced pressure and purified by flash chromatography on KPNH(EtOAc: hexane, gradient from 40 to 70%) followed by a secondpurification by preparative HPLC to give the title compounds as a whitesolid (17 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.78 (s,1H), 8.53 (t, J=1.8 Hz, 1H), 8.27-8.12 (m, 2H), 7.98-7.87 (m, 2H), 7.74(dt, J=7.7, 1.4 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H),4.81 (h, J=8.0 Hz, 1H), 3.96 (d, J=34.9 Hz, 6H), 2.18-2.05 (m, 2H),1.96-1.81 (m, 2H); HPLC: 98.0% (254 nm); LC/MS: 386.2 (M+H).

Example 28:2-Aminomethyl-2-(2-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-ethyl)-propane-1,3-diolStep 1:6-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-2-aza-spiro[3.3]heptane-2-carboxylicAcid Tert-Butyl Ester

A mixture of6-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (190 mg; 0.47 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(160 mg; 0.56 mmol; 1.20 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (38mg; 0.05 mmol; 0.10 eq.), cesium carbonate (229 mg; 0.70 mmol; 1.50 eq.)in dioxane (3.00 mL) and water (0.30 mL) was stirred at 120° C.overnight in a sealed tube. The mixture was then concentrated underreduced pressure and purified by flash chromatography on silica (MeOH:EtOAc, gradient from 0:100 to 20:80) to give the title compound as ayellow solid (156 mg, 63%). LC/MS: 527.3 (M+H).

Step 2:2-Aminomethyl-2-(2-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-ethyl)-propane-1,3-diol

Hydrogen chloride (0.71 mL of a 2 M solution in Et2O; 1.42 mmol; 5.00eq.) was added to a solution of6-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (150 mg; 0.28 mmol; 1.00 eq.) in methanol (3.00mL). The reaction mixture was then stirred at rt overnight.

LCMS analysis of the reaction mixture indicated that the reaction wascomplete but major product appeared to be a ring-opening by-product.Reaction mixture was concentrated under reduced pressure and purified bypreparative HPLC to afford the title compound as a white solid (13 mg,10%). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=1.9 Hz, 1H), 8.25-8.15 (m,3H), 8.06 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.66 (d, J=7.7 Hz, 1H),7.47 (t, J=7.6 Hz, 1H), 6.77 (d, J=6.3 Hz, 1H), 4.73 (m, 1H), 3.99-3.86(m, 7H), 2.67 (s, 2H), 2.35-2.27 (m, 2H), 2.05-1.96 (m, 2H); HPLC: 97.0%(254 nm); LC/MS: 463.3 (M+H).

Compounds below were prepared following similar routes and protocols:

Exam- Structure ple Analyticals

29 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)372.2. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.78 (s, 1H), 8.61 (t,J = 1.8 Hz, 1H), 8.25 (d, J = 8.2 Hz, 2H), 7.99-7.87 (m, 2H), 7.77 (dt,J = 7.7, 1.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 2.4 Hz,1H), 3.94 (d, J = 23.6 Hz, 6H), 3.26 (tq, J = 7.5, 3.9 Hz, 1H), 0.98(td, J = 7.0, 4.9 Hz, 2H), 0.75-0.68 (m, 2H).

30 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)372.2. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, J = 1.8 Hz, 1H), 8.28-8.17(m, 3H), 8.01 (s, 1H), 7.88 (s, 1H), 7.74-7.64 (m, 2H), 7.47 (t, J = 7.7Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 3.90 (s, 5H), 3.01 (tq, J = 7.2, 3.7Hz, 1H), 0.82 (td, J = 7.0, 4.7 Hz, 2H), 0.69-0.63 (m, 2H).

31 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)386.2. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 1.8 Hz, 1H), 8.23-8.16(m, 3H), 8.06 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.66 (dt, J = 7.6,1.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 4.72(h, J = 8.0 Hz, 1H), 3.92 (d, J = 10.2 Hz, 6H), 2.36 (ddt, J = 14.6,10.5, 5.2 Hz, 2H), 2.16 (pd, J = 9.5, 5.4 Hz, 2H), 1.83-1.71 (m, 2H).

32 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)400.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 1.8 Hz, 1H), 8.23-8.17(m, 3H), 8.04 (s, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 0.8 Hz,1H), 7.66 (dt, J = 7.7, 1.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.20 (d,J = 6.8 Hz, 1H), 4.56 (h, J = 7.0 Hz, 1H), 3.91 (d, J = 9.6 Hz, 6H),2.09 (dt, J = 7.7, 4.5 Hz, 2H), 1.76-1.59 (m, 7H).

33 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)400.3. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 30.3 Hz, 2H), 8.54 (t, J= 1.7 Hz, 1H), 8.26-8.17 (m, 2H), 7.88 (dd, J = 4.5, 1.6 Hz, 2H), 7.67(dt, J = 7.7, 1.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 2.4Hz, 1H), 4.63 (h, J = 6.5 Hz, 1H), 3.93 (d, J = 19.6 Hz, 6H), 2.24-2.12(m, 2H), 1.84-1.57 (m, 4H).

34 yellow solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)375.3. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 1.8 Hz, 1H), 8.43-8.03(m, 9H), 7.88 (d, J = 16.6 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 3.94 (d, J= 13.7 Hz, 7H), 3.18 (h, J = 6.3 Hz, 2H).

35 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)390.2. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.20 (t, J = 6.4 Hz,3H), 8.04 (s, 1H), 7.89 (s, 1H), 7.79-7.62 (m, 2H), 7.47 (t, J = 7.7 Hz,1H), 6.75 (t, J = 5.6 Hz, 1H), 4.66 (d, J = 4.7 Hz, 1H), 3.91 (d, J =8.9 Hz, 6H), 3.60 (dq, J = 21.8, 5.8, 5.2 Hz, 4H), 1.84 (p, J = 6.5 Hz,2H).

36 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)445.3. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 1.7 Hz, 1H), 8.26-8.15(m, 3H), 8.05 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.66 (dd, J = 7.7,1.6 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 6.63 (t, J = 5.4 Hz, 1H),3.92 (dd, J = 13.9, 1.2 Hz, 6H), 3.67 (q, J = 6.4 Hz, 2H), 3.62-3.55 (m,4H), 2.60 (t, J = 6.8 Hz, 2H), 2.48 (d, J = 4.7 Hz, 3H).

37 off-white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)423.2. 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.44 (m, 2H), 8.27 (dd, J = 7.0,1.4 Hz, 2H), 8.13 (s, 1H), 8.07 (s, 1H), 8.01 (dd, J = 7.8, 1.5 Hz, 1H),7.85-7.77 (m, 2H), 7.64-7.58 (m, 1H), 7.48-7.36 (m, 4H), 4.73 (d, J =5.7 Hz, 2H), 3.93 (dd, J = 17.4, 1.2 Hz, 6H).

38 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)445.2. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.6 Hz, 1H), 8.27-8.19(m, 3H), 8.01 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.69-7.64 (m, 1H),7.46 (td, J = 7.8, 1.2 Hz, 1H), 6.82 (t, J = 5.9 Hz, 1H), 4.17 (dd, J =8.9, 6.9 Hz, 2H), 3.91 (dd, J = 11.4, 1.3 Hz, 6H), 3.70 (ddd, J = 23.0,10.5, 6.8 Hz, 4H), 3.49 (t, J = 6.2 Hz, 2H).

39 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)443.2. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 1.7 Hz, 1H), 8.29 (s,1H), 8.26-8.19 (m, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H),7.69-7.64 (m, 1H), 7.49-7.43 (m, 1H), 6.76 (t, J = 5.9 Hz, 1H), 3.91(dd, J = 9.1, 1.3 Hz, 6H), 3.71 (q, J = 6.1 Hz, 2H), 3.48 (dt, J = 13.4,6.6 Hz, 4H), 2.15 (t, J = 8.0 Hz, 2H), 1.82 (p, J = 7.7 Hz, 2H).

40 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)457.3. 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.46 (m, 1H), 8.26-8.15 (m, 3H),8.09 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.69-7.63 (m, 1H), 7.47 (t, J= 7.8 Hz, 1H), 6.72 (t, J = 5.9 Hz, 1H), 3.91 (dd, J = 8.4, 1.2 Hz, 6H),3.52 (q, J = 6.5 Hz, 2H), 3.37 (t, J = 7.0 Hz, 2H), 2.23 (t, J = 8.0 Hz,2H), 1.88 (dp, J = 20.8, 7.2 Hz, 4H).

41 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)402.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (q, J = 1.5 Hz, 1H), 8.26 (d, J= 1.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 2H), 8.06 (s, 1H), 7.89 (s, 1H),7.76 (s, 1H), 7.67 (dd, J = 7.7, 1.6 Hz, 1H), 7.52- 7.45 (m, 1H), 6.47(d, J = 6.0 Hz, 1H), 4.77 (h, J = 5.6 Hz, 1H), 4.11-4.04 (m, 1H), 3.91(dd, J = 9.0, 1.1 Hz, 7H), 3.78 (td, J = 8.3, 6.6 Hz, 1H), 3.69 (dd, J =8.8, 4.7 Hz, 1H), 2.29 (ddd, J = 15.1, 13.5, 7.5 Hz, 1H), 2.11- 2.01 (m,1H).

42 white solid. HPLC(Column): (254 nm) 100%; (NMR looks 100%.).LC/MS(Column): (M + H) 436.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J =1.7 Hz, 1H), 8.23-8.16 (m, 3H), 8.02 (s, 1H), 7.88 (s, 1H), 7.73 (s,1H), 7.69-7.64 (m, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.89 (t, J = 6.0 Hz,1H), 3.91 (dd, J = 12.9, 1.2 Hz, 6H), 3.70 (t, J = 6.2 Hz, 2H),2.74-2.57 (m, 3H).

43 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)414.3. 1H NMR (400 MHz, DMSO-d6) δ 8.55-8.48 (m, 1H), 8.25-8.14 (m, 3H),8.03 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.65 (dd, J = 7.6, 1.6 Hz,1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 6.57 (t, J = 6.3 Hz, 1H), 3.92 (dd,J = 14.4, 1.2 Hz, 6H), 3.64 (d, J = 6.1 Hz, 2H), 2.06 (dt, J = 9.8, 7.6Hz, 2H), 1.87 (p, J = 7.5 Hz, 2H), 1.65 (q, J = 8.3, 7.8 Hz, 2H), 1.18(d, J = 1.2 Hz, 3H).

44 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)429.2. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 1.8 Hz, 1H), 8.26-8.14(m, 3H), 8.08 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.69-7.62 (m, 1H),7.47 (t, J = 7.7 Hz, 1H), 5.91 (d, J = 7.0 Hz, 1H), 4.20 (qd, J = 8.5,7.8, 4.5 Hz, 1H), 3.92 (d, J = 17.0 Hz, 6H), 2.91 (p, J = 4.8 Hz, 1H),1.89 (dtd, J = 13.2, 9.8, 9.2, 3.8 Hz, 2H), 1.76-1.60 (m, 4H), 1.45 (dp,J = 15.2, 6.2, 5.2 Hz, 2H).

45 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)434.2. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.37-8.32 (m, 1H),8.25- 8.18 (m, 2H), 7.96-7.89 (m, 2H), 7.69 (d, J = 7.7 Hz, 1H),7.62-7.57 (m, 1H), 7.53-7.46 (m, 1H), 4.71 (td, J = 23.2, 8.3 Hz, 4H),4.34 (d, J = 21.9 Hz, 2H), 3.96- 3.86 (m, 6H), 2.91-2.82 (m, 3H).

46 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)402.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.26-8.14 (m, 3H),8.09- 8.03 (m, 1H), 7.91-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.66 (d, J =7.6 Hz, 1H), 7.48 (ddd, J = 9.1, 5.3, 2.1 Hz, 1H), 6.60 (dd, J = 6.1,2.3 Hz, 1H), 5.04 (s, 1H), 4.74 (q, J = 6.9 Hz, 1H), 4.39-4.29 (m, 1H),3.98-3.84 (m, 5H), 2.45-2.36 (m, 2H), 2.29 (td, J = 9.4, 8.9, 3.8 Hz,2H).

47 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)402.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.8 Hz, 1H), 8.25-8.15(m, 3H), 8.05 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.69-7.62 (m, 1H),7.47 (t, J = 7.7 Hz, 1H), 6.55 (d, J = 6.5 Hz, 1H), 5.06 (s, 1H), 4.17(h, J = 7.9 Hz, 1H), 3.91 (d, J = 9.7 Hz, 7H), 2.76-2.66 (m, 2H),2.07-1.96 (m, 2H).

48 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)422.2. 1H NMR (400 MHz, DMSO-d6) δ 8.53-8.45 (m, 1H), 8.28 (d, J = 1.3Hz, 1H), 8.19 (d, J = 10.7 Hz, 2H), 8.06 (s, 1H), 7.88 (s, 1H), 7.76 (s,1H), 7.70-7.64 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 6.1 Hz,1H), 4.55 (hept, J = 7.3 Hz, 1H), 3.92 (dd, J = 13.0, 1.3 Hz, 5H),3.10-2.81 (m, 4H).

49 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)464.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.28-8.16 (m, 3H),8.07- 8.01 (m, 1H), 7.94-7.89 (m, 1H), 7.77-7.72 (m, 1H), 7.67 (d, J =7.8 Hz, 1H), 7.48 (ddd, J = 7.9, 4.7, 1.7 Hz, 1H), 6.99-6.92 (m, 1H),4.69 (hept, J = 8.4, 7.7 Hz, 1H), 3.96-3.81 (m, 7H), 2.96-2.87 (m, 3H),2.72 (q, J = 8.8 Hz, 2H), 2.49-2.42 (m, 2H).

50 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)404.2. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 1.6 Hz, 1H), 8.27-8.15(m, 3H), 8.06 (d, J = 3.5 Hz, 1H), 7.89 (d, J = 9.4 Hz, 1H), 7.76 (d, J= 7.3 Hz, 1H), 7.70-7.63 (m, 1H), 7.48 (q, J = 7.2 Hz, 1H), 6.82 (t, J =5.6 Hz, 1H), 5.42-5.35 (m, 0H), 5.25 (td, J = 6.1, 3.1 Hz, 0H), 5.06 (p,J = 6.8 Hz, 0H), 4.96-4.82 (m, 1H), 4.28 (q, J = 8.0 Hz, 0H), 3.96-3.87(m, 6H), 2.85 (pd, J = 6.8, 3.3 Hz, 1H), 2.61 (dddd, J = 17.3, 12.9,9.1, 4.9 Hz, 2H), 2.49-2.36 (m, 1H).

51 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)459.3. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 1.7 Hz, 1H), 8.24-8.13(m, 3H), 8.04 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.70-7.62 (m, 1H),7.47 (t, J = 7.7 Hz, 1H), 6.77 (t, J = 5.6 Hz, 1H), 3.91 (d, J = 9.3 Hz,6H), 3.64-3.46 (m, 6H), 2.37 (dt, J = 20.1, 5.7 Hz, 6H), 1.81 (h, J =6.9 Hz, 2H).

52 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)418.2. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 1.8 Hz, 1H), 8.28-8.15(m, 3H), 8.07 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.72-7.64 (m, 1H),7.48 (t, J = 7.7 Hz, 1H), 6.63 (t, J = 6.0 Hz, 1H), 6.08 (s, 1H), 4.60(d, J = 6.1 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.01-3.85 (m, 8H).

53 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)430.3. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.7 Hz, 1H), 8.26-8.16(m, 3H), 8.01 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.69-7.63 (m, 1H),7.48 (t, J = 7.7 Hz, 1H), 6.76 (t, J = 5.6 Hz, 1H), 5.02 (s, 1H), 3.91(d, J = 9.2 Hz, 7H), 3.75 (d, J = 5.5 Hz, 2H), 3.52 (s, 2H), 1.96-1.76(m, 6H).

54 white solid. HPLC(Column): (254 nm) 96.1%. LC/MS(Column): (M + H)4061H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 1.7 Hz, 1H), 8.25-8.16 (m,3H), 8.06 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.70-7.63 (m, 1H), 7.47(t, J = 7.7 Hz, 1H), 6.53 (t, J = 5.3 Hz, 1H), 4.97-4.89 (m, 1H),4.79-4.71 (m, 1H), 3.97-3.76 (m, 7H), 3.45 (h, J = 5.4 Hz, 3H).

55 off-white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)493.2. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.7 Hz, 1H), 8.25-8.15(m, 3H), 8.05 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.69-7.63 (m, 1H),7.48 (t, J = 7.7 Hz, 1H), 6.69-6.60 (m, 1H), 3.92 (d, J = 12.1 Hz, 6H),3.67 (q, J = 6.4 Hz, 2H), 3.04 (d, J = 2.8 Hz, 8H), 2.80 (t, J = 6.7 Hz,2H).

56 white solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)406.9. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.3 Hz, 1H), 8.26-8.16(m, 3H), 8.09-8.03 (m, 1H), 7.93-7.88 (m, 1H), 7.79- 7.73 (m, 1H), 7.66(d, J = 7.7 Hz, 1H), 7.50-7.42 (m, 1H), 7.27 (s, 1H), 6.80-6.45 (m, 2H),4.96-4.89 (m, 1H), 4.79-4.71 (m, 1H), 3.98-3.76 (m, 8H), 3.45 (q, J =7.2 Hz, 3H).

57 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)417.85. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.36-8.29 (m, 1H),8.25- 8.18 (m, 2H), 8.08-8.00 (m, 2H), 7.97-7.91 (m, 1H), 7.78-7.73 (m,1H), 7.66 (d, J = 7.8 Hz, 1H), 7.45 (ddd, J = 9.0, 5.4, 2.2 Hz, 1H),6.74 (d, J = 6.1 Hz, 1H), 3.95- 3.86 (m, 6H), 3.62 (dt, J = 6.7, 3.7 Hz,2H), 3.41-3.35 (m, 2H), 1.84-1.78 (m, 3H).

58 yellow solid. HPLC(Column): (254 nm) 82%. LC/MS(Column): (M + H)444.9. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.3 Hz, 1H), 8.29-8.18(m, 3H), 8.06-8.01 (m, 1H), 7.92-7.88 (m, 1H), 7.77- 7.71 (m, 1H), 7.66(d, J = 8.0 Hz, 1H), 7.46 (ddd, J = 9.4, 5.5, 1.8 Hz, 1H), 6.71 (q, J =5.0, 4.4 Hz, 1H), 6.29 (s, 1H), 3.94-3.86 (m, 6H), 3.71-3.62 (m, 2H),3.51-3.44 (m, 2H), 3.41-3.35 (m, 2H), 3.22-3.15 (m, 2H).

59 off-white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)431.85. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.25-8.13 (m, 3H),8.06- 8.00 (m, 1H), 7.90-7.85 (m, 1H), 7.76-7.70 (m, 1H), 7.66 (d, J =7.8 Hz, 1H), 7.48 (ddd, J = 9.3, 5.4, 1.7 Hz, 1H), 6.61 (d, J = 6.2 Hz,1H), 3.95-3.84 (m, 6H), 3.79- 3.68 (m, 2H), 3.66-3.57 (m, 1H), 3.47(ddd, J = 24.3, 11.9, 6.9 Hz, 2H), 2.88 (d, J = 12.2 Hz, 1H), 2.64 (d, J= 9.5 Hz, 2H), 2.47-2.41 (m, 1H).

60 light brown solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)429.3.

61 light brown solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)429.3.

62 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)402.3. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.23-8.15 (m, 3H), 8.05(s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47 (t,J = 7.7 Hz, 1H), 6.46 (d, J = 6.8 Hz, 1H), 4.26 (h, J = 8.1 Hz, 1H),3.91 (d, J = 11.8 Hz, 6H), 3.11 (q, J = 7.9 Hz, 1H), 2.69 (q, J = 8.4Hz, 2H), 1.82-1.73 (m, 2H).

63 brown solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)403.3. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.9 Hz, 1H), 8.24-8.14(m, 3H), 8.02 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 1.5 Hz,1H), 7.66 (d, J = 7.7 Hz, 1H), 7.47 (td, J = 7.8, 1.6 Hz, 1H), 6.93-6.85(m, 1H), 4.68 (td, J = 6.7, 5.7, 1.6 Hz, 2H), 4.47 (td, J = 5.9, 1.6 Hz,2H), 3.95-3.81 (m, 8H), 3.42-3.35 (m, 1H).

64 brown solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)415.3.

65 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)441.3.

66 off-white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)427.3. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.24-8.12 (m, 3H), 8.02(d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.75-7.62 (m, 2H), 7.50(dt, J = 9.9, 5.0 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 13.7 Hz, 2H), 3.91(t, J = 3.2 Hz, 6H), 2.06 (t, J = 6.2 Hz, 2H), 1.94-1.86 (m, 2H),1.74-1.60 (m, 4H).

67 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)459.3. 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.67 (m, 2H), 8.53 (d, J = 2.2Hz, 1H), 8.26-8.17 (m, 2H), 7.93-7.85 (m, 2H), 7.68 (d, J = 7.7 Hz, 1H),7.52-7.45 (m, 1H), 6.95 (d, J = 2.4 Hz, 1H), 4.27-4.18 (m, 2H),3.99-3.87 (m, 6H), 3.78- 3.69 (m, 2H), 3.62-3.54 (m, 2H), 1.99-1.90 (m,2H).

68 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)390.2. 1H NMR (400 MHz, DMSO-d6) δ 8.78-8.64 (m, 2H), 8.55 (d, J = 1.9Hz, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.93-7.84 (m, 2H), 7.67 (d, J = 7.7Hz, 1H), 7.52-7.44 (m, 1H), 6.94 (d, J = 2.4 Hz, 1H), 4.70-4.63 (m, 1H),3.98-3.88 (m, 6H), 3.82- 3.72 (m, 2H), 3.65-3.58 (m, 2H), 1.92-1.83 (m,2H).

69 off-white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)445.3. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 5.4 Hz, 1H), 8.76 (d, J= 2.1 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.27-8.18 (m, 2H), 7.93-7.85(m, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.48 (td, J = 7.9, 2.4 Hz, 1H), 6.94(d, J = 2.4 Hz, 1H), 4.01-3.96 (m, 3H), 3.92-3.88 (m, 3H), 3.86-3.79 (m,2H), 3.66 (t, J = 4.1 Hz, 4H), 2.70-2.63 (m, 2H).

70 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)443.3.

71 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)414.3.

72 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)457.3.

73 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)417.3.

74 pink solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)443.3.

75 gray solid. HPLC(Column): (254 nm) 89%. LC/MS(Column): (M + H) 459.3.

76 brown solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)443.3.

77 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)427.3.

78 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)459.3. 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.39 (m, 1H), 8.16-8.08 (m, 3H),7.98 (d, J = 0.9 Hz, 1H), 7.82 (d, J = 0.9 Hz, 1H), 7.68 (d, J = 0.9 Hz,1H), 7.58 (ddd, J = 7.7, 1.9, 1.2 Hz, 1H), 7.42-7.37 (m, 1H), 6.64 (t, J= 5.8 Hz, 1H), 4.19-4.13 (m, 2H), 3.83 (d, J = 8.8 Hz, 6H), 3.53-3.46(m, 4H), 3.22 (t, J = 7.0 Hz, 2H), 1.83 (p, J = 7.0 Hz, 2H).

79 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)464.3.

80 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)404.2.

81 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)436.3.

82 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)402.2.

83 white solid. HPLC: (254 nm) 91%. LC/MS: (M + H) 406.2.

84 white solid. HPLC: (254 nm) 97.5%. LC/MS: (M + H) 493.

85 white solid. HPLC: (254 nm) 90%. LC/MS: (M + H) 429.3.

Example 86:1-Methyl-8-(4-{2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-[(piperidin-4-ylmethyl)-amino]-pyrimidin-5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-oneHydrochloride Step 1:4-({2-Chloro-5-[1-(1-methyl-2-oxo-1-aza-spiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

A mixture of8-(4-Bromo-pyrazol-1-yl)-1-methyl-1-aza-spiro[4.5]decan-2-one (410 mg;1.31 mmol; 1.00 eq.),4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (366 mg;1.44 mmol; 1.10 eq.), Potassium acetate (193 mg; 1.97 mmol; 1.50 eq.)and PdCl₂(PPh₃)₂ (9 mg; 0.01 mmol; 0.01 eq.) in Dioxane (7.50 mL) wasstirred at 100° C. under N2 atmosphere for 22 h. The reaction mixturewas cooled to room temperature and treated with 0.5× the amounts ofreagents added originally (except for bromide sm) and stirred at 100° C.for 29 h. It was cooled to room temperature and4-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (586 mg; 1.44 mmol; 1.10 eq.) in dioxane (2 mL),and K₂CO₃ (544 mg; 3.94 mmol; 3.00 eq.) in water (2.50 mL) were added.Nitrogen was bubbled through the solution for 5 min, PdCl₂(PPh₃)₂ (9 mg;0.01 mmol; 0.01 eq.) was added and the mixture was stirred at 90° C.overnight. It was cooled to room temperature and diluted with EtOAc (10mL) and water (2 mL). The aqueous layer was removed and the organiclayer was filtered and concentrated. Purification by flashchromatography on silica (EtOAc:Hexane, gradient from 20 to 70% thenMeOH:DCM, 10:90) afforded the title compound as a golden foam (390 mg,32%). LC/MS: 559 (M+H).

Step 2:methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

A mixture of4-({2-Chloro-5-[1-(1-methyl-2-oxo-1-aza-spiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (390 mg; 0.42 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(179 mg; 0.63 mmol; 1.50 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (34mg; 0.04 mmol; 0.10 eq.) and cesium carbonate (629 μl; 1.26 mmol; 3.00eq.) in dioxane (6.0 mL) was stirred at 100° C. under nitrogenatmosphere overnight. The reaction mixture was then cooled to roomtemperature and diluted with EtOAc (10 mL) and water (3 mL). The organiclayer was separated, filtered through celite and concentrated underreduced pressure. Purification by flash chromatography (EtOAc, 100% thenMeOH:DCM, gradient from 0 to 10%) afforded the title compound as agolden oil (229 mg, 80%). ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.23(s, 1H), 8.18 (d, 2H), 8.12 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.65(d, 1H), 7.47 (t, 1H), 6.76 (t, 1H), 4.27 (m, 1H), 4.02-3.91 (m, 2H),3.90 (s, 3H), 3.47 (t, 2H), 2.71 (m, 1H), 2.68 (s, 3H), 2.28 (t, 2H),2.14 (d, 2H), 2.10-1.86 (m, 6H), 1.73 (d, 2H), 1.55 (d, 2H), 1.39 (s,9H), 1.13 (qd, 2H). LC/MS: 680 (M+1).

Step 3:1-Methyl-8-(4-{2-[3-(-methyl-1H-pyrazol-4-yl)-phenyl]-4-[(piperidin-4-ylmethy)-amino]-pyrimidin-5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-oneHydrochloride

Hydrogen chloride (0.71 mL of a 2 M solution in Et₂O; 1.42 mmol; 5.00eq.) was added to a solution of4-({5-[1-(1-Methyl-2-oxo-1-aza-spiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (225 mg; 0.33 mmol; 1.00 eq.) in MeOH (3 mL).Reaction mixture was stirred 2 h at room temperature. It was thendiluted in Et20 and filtered. The solid was dried under high vacuum toyield the title compound a white solid (180 mg, 79%). ¹H NMR (400 MHz,DMSO-d6) δ 8.93 (brs, 2H), 8.68 (s, 1H), 8.64 (m, 1H), 8.37 (s, 1H),8.33 (s, 1H), 8.23 (s, 1H), 8.17 (d, 1H), 8.06 (s, 1H), 7.91 (d, 2H),7.65 (t, 1H), 4.32 (m, 1H), 3.64 (t, 2H), 3.28 (d, 2H), 2.93-2.77 (m,2H), 2.68 (s, 3H), 2.28 (t, 2H), 2.20-1.91 (m, 9H), 1.91-1.80 (d, 2H),1.57 (m, 4H). LC/MS: 580 (M+1).

Example 87:1-Methyl-8-(4-{4-[(1-methyl-piperidin-4-ylmethyl)-amino]-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one

Iodomethane (stabilised with silver, 5 μl; 79.81 μmol; 1.10 eq.) wasadded dropwise to a solution of1-Methyl-8-(4-{2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-[(piperidin-4-ylmethyl)-amino]-pyrimidin-5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-onehydrochloride (3) (50 mg; 0.07 mmol; 1.00 eq.) and TEA (40 μl; 0.29mmol; 4.00 eq.) in N,N-Dimethylformamide (3.0 mL). The clear solutionwas stirred overnight at RT concentrated under reduced pressure andpurified by prep HPLC (C-18 (10 um), 30×150 mm, 0.1% NH4OH modifiedmobile phases (A=water, B=ACN), Method 25 to 75% ACN over 25 min at 60mL/min) to afford the title compound as a white solid (8 mg, 17%). ¹HNMR (500 MHz, DMSO-d6) δ 8.49 (t, 1H), 8.21 (s, 1H), 8.16 (d, 2H), 8.10(s, 1H), 7.84 (s, 1H), 7.76 (s, 1H), 7.66-7.61 (m, 1H), 7.46 (t, 1H),6.73 (t, 1H), 4.31-4.19 (m, 1H), 3.88 (s, 3H), 3.44 (t, 2H), 2.75 (d,2H), 2.66 (s, 3H), 2.26 (t, 2H), 2.11 (s, 5H), 2.05-1.88 (m, 6H),1.85-1.72 (m, 3H), 1.68 (d, 2H), 1.52 (d, 2H), 1.27 (m, 2H); LC/MS: 594(M+1).

Compounds below were prepared following similar routes and protocols:

Structure Example Analyticals

 88 brown solid. HPLC: (254 nm) 80%. LC/MS: (M + H) 403.8.

 89 Brown solid. HPLC: (254 nm) 91%. LC/MS: (M + H) 389.8.

 90 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)422.7.

 91 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)445.7.

 92 yellow solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)418.8.

 93 off-white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)417.75.

 94 white solid. Racemic. Trans isomer. HPLC(Column): (254 nm) 99%.LC/MS(Column): (M + H) 416.8.

 95 white solid. Racemic-trans isomer. HPLC(Column): (254 nm) 98%.LC/MS(Column): (M + H) 416.75.

 96 HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H) 376.75.

 97 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)404.75.

 98 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)440.75.

 99 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)464.75.

100 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)376.25.

101 yellow solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)404.3.

102 hite solid. HPLC(Column): (254 nm) 92%. LC/MS(Column): (M + H)429.3.

103 HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H) 429.3.

104 off-white solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)415.3.

105 brown solid. HPLC: (254 nm) 98.7%. LC/MS(Column): (M + H) 445.3.

106 Pale yellow solid. HPLC(Xbridge): (percent area) 93.8%.LC/MS(Column): (M + H)518.2. 1H NMR (400 MHz, MeOD): 8.90 (s, 1H), 8.59(s, 1H), 8.29 (d, J = 7.84 Hz, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.75 (d,J = 9.48 Hz, 1H), 7.53 (t, J = 7.76 Hz, 1H), 4.57-4.53 (m, 1H), 4.36 (s,1H), 4.22-4.11 (m, 7H), 3.97 (s, 3H), 3.86-3.83 (m, 2H), 3.75-3.74 (m,1H), 3.65-3.53 (m, 1H), 3.32-3.31 (m, 1H), 2.14-2.11 (m, 3H).

107 white solid. Racemic-Cis isomer. . HPLC(Column): (254 nm) 96%.LC/MS(Column): (M + H) 415.3

108 white solid. Racemic. Cis isomer. HPLC(Column): (254 nm) 93.4%.LC/MS(Column): (M + H) 415.3.

109 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)431.3.

110 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)459.5

111 white solid. Cis isomer. HPLC(Column): (254 nm) 100%. LC/MS(Column):(M + H) 429.3.

112 white solid. HPLC(Column): (percent area) 100%. LC/MS(Column): (M +H) 473.4.

113 white solid. Racemic. Cis isomer. HPLC(Column): (254 nm) 100%.LC/MS(Column): (M + H) 417.3.

114 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)473.35.

115 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)431.3.

116 white solid. Racemic. Cis isomer. HPLC(Column): (254 nm) 97%.LC/MS(Column): (M + H) 445.3.

117 white solid. HPLC(Column): (254 nm) 92%. LC/MS(Column): (M + H)401.3.

118 Brown solid. HPLC(Column UPLC): 91%. LC/MS(Column): (M + H) 417.4

119 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)402.3.

120 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)406.3.

121 white solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)401.3.

122 off-white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)444.3.

123 off-white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)444.3.

124 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)401.3.

125 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)429.3.

126 white solid. Racemic. Cis isomer. HPLC(Column): (254 nm) 99%.LC/MS(Column): (M + H) 445.3.

127 Off white Solid. HPLC(Xbridge): (254 nm) 94.1%. LC/MS(Column): (M +H) 511.0. 400 MHz, DMSO-d6: 9.34-9.32 (m, 1H), 8.80 (s, 1H), 8.54 (s,1H), 8.25-8.21 (m, 1H), 7.90 (s, 1H), 7.72 (d, J = 7.68 Hz, 1H), 7.51(t, J = 7.72 Hz, 1H), 3.89 (s, 3H), 3.87-3.87 (m, 2H), 3.32 (m, 4H),3.12-3.06 (m, 4H), 2.86 (t, J = 6.16 Hz, 2H), 2.50-2.49 (m, 3H), 2.45(s, 1H)

128 Off white solid. HPLC(Xbridge): (254 nm) 93.1%. LC/MS(Column): (M +H) 447.0. 1H NMR (400 MHz, DMSO-d6): 8.92 (d, J = 6.80 Hz, 1H), 8.83 (s,1H), 8.54 (s, 1H), 8.22-8.21 (m, 2H), 7.88 (s, 1H), 7.74 (d, J = 7.96Hz, 1H), 7.53 (t, J = 7.80 Hz, 1H), 3.90 (s, 3H), 2.80 (s, 3H), 2.07 (d,J = 10.08 Hz, 2H), 1.71-0.00 (m, 1H), 1.63-1.51 (m, 4H), 1.36-0.00 (m,4H), 1.16-1.14 (m, 1H)

129 Off white solid. HPLC(Column): (Xbrdge) 98.8%. LC/MS(Column): (M +H) 525.2. 1H-NMR (400 MHz, DMSO-d6): 9.14 (d, J = 7.20 Hz, 1H), 8.83 (s,1H), 8.54 (s, 1H), 8.21-8.24 (m, 2H), 7.90 (s, 1H), 7.73 (d, J = 7.60Hz, 1H), 7.52 (t, J = 8.00 Hz, 1H), 7.22 (d, J = 6.80 Hz, 1H), 4.45-4.48(m, 1H), 3.91 (s, 3H), 3.34-3.35 (m, 1H), 2.95 (s, 3H), 2.82 (s, 3H).

130 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)433.3.

131 brown solid. Racemic. HPLC(Column): (254 nm) 95%. LC/MS(Column):(M + H) 446.3.

132 brown solid. Racemic. HPLC(Column): (254 nm) 93%. LC/MS(Column):(M + H) 446.3.

Example 133 and 134:(1R,2S,3R)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexane-1,2-dioland(1S,2R,6R)-2-Amino-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yloxy}-cyclohexanol(Racemics—Relative Configuration)

A suspension of a racemic mixture of (1S,2R,3S) and(1R,2S,3R)-3-[2-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamino]-cyclohexane-1,2-diol(390 mg; 1.20 mmol; 1.00 eq.),1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole(411 mg; 1.45 mmol; 1.20 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (98mg; 0.12 mmol; 0.10 eq.) and cesium carbonate (589 mg; 1.81 mmol; 1.50eq.) in dioxane (4 mL) and water (0.4 mL) was stirred at 120° C.overnight in a sealed tubed. The reaction mixture was then cooled to RT,filtered through a celite pad, concentrated and purified by prep-HPLC(23-25% CH₃CN in 0.1% NH₄OH in H₂O) to give the title compound (175 mg,36%), as a racemic mixture of (1S,2R,3R) and(1R,2S,3R)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexane-1,2-diol(175.00 mg; 0.39 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ8.53 (s, 1H), 8.23-8.15 (m, 3H), 8.07 (s, 1H), 7.86 (s, 1H), 7.78 (s,1H), 7.66 (d, J=7.7 Hz, 1H), 7.48 (t, J=8.5 Hz, 1H), 6.06 (d, J=6.8 Hz,1H), 4.59 (d, J=6.4 Hz, 1H), 4.52-4.48 (m, 1H), 4.40 (m, 1H), 3.93 (s,3H), 3.90 (s, 3H), 3.63-3.56 (m, 1H), 2.21-2.11 (m, 1H), 1.77 (m, 2H),1.48-1.26 (m, 3H). LC/MS446.2 (M+H).

A second fraction containing a racemic mixture of (1S,2R,3R) and(1S,2R,6R)-2-Amino-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yloxy}-cyclohexanol(O-alkylation side-product) was isolated as a white solid (24 mg). 1HNMR (400 MHz, DMSO-d6) 8.49 (s, 1H), 8.25 (s, 1H), 8.20-8.14 (m, 2H),8.07 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.65 (d, J=7.7 Hz, 1H),7.50-7.44 (m, 1H), 6.69 (s, 1H), 5.07-4.84 (m, 2H), 4.40 (s, 1H), 3.95(s, 3H), 3.88 (s, 3H), 3.74 (m, 2H), 1.64 (m, 4H), 1.52 (s, 1H), 1.31(s, 1H). LC/MS: 446.3 (M+H).

Compounds below were prepared following similar routes and protocols:

Structure Example Analyticals

135 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)418.3.

136 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)464.3.

137 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)416.3.

138 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)416.3.

139 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)432.3.

140 white solid HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)432.3.

141 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)450.3.

142 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)450.3.

143 white solid. HPLC(Column): (254 nm) 93%. LC/MS(Column): (M + H)429.3.

144 white solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)415.3.

145 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)415.3.

146 Off white solid. HPLC(X-Bridge): (254 nm) 98.8%. LC/MS(Column): (M +H) 463.3. 1H NMR (DMSO-d6, 400 MHz): ppm 9.29 (s, 1H), 8.78 (s, 1H),8.54 (s, 1H), 8.25-8.21 (m, 2H), 7.92-7.90 (m, 1H), 7.81-7.71 (m, 1H),7.51 (d, J = 7.6 Hz, 1H), 4.16 (s, 1H), 3.89-3.80 (m, 5H), 3.62-3.59 (m,4H), 3.58-3.48 (m, 1H), 3.31-3.21 (m, 1H), 2.81 (s, 3H), 2.66-2.49 (m,3H).

147 white solid. Off white solid. HPLC(Column): (254 nm) 98%.LC/MS(Column): (M + H) 430.4.

148 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)401.2.

149 white solid. Trans isomer. HPLC: (254 nm) 90%. LC/MS(Column): (M +H) 430.1. 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 8.19 (ddd, J = 13.7,6.8, 4.1 Hz, 3H), 8.03 (d, J = 2.4 Hz, 1H), 7.88-7.84 (m, 1H), 7.76-7.71(m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.51-7.46 (m, 1H), 6.08 (d, J = 7.8Hz, 1H), 4.58 (t, J = 3.1 Hz, 1H), 4.10 (d, J = 9.9 Hz, 1H), 3.94-3.89(m, 6H), 3.45 (s, 1H), 2.02 (d, J = 12.4 Hz, 2H), 1.91 (d, J = 12.1 Hz,2H), 1.42 (dq, J = 41.7, 12.5 Hz, 4H).

150 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)441.3.

151 Pale yellow solid. HPLC(Xbridge): (254 nm) 91.3%. LC/MS(Column):(M + H) 511.2.

152 white solid. HPLC(Column): (254 nm) 83%. LC/MS(Column): (M + H)469.3.

153 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)469.3.

154 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)441.3.

155 white solid. Trans isomer. HPLC(Column): (254 nm) 95%.LC/MS(Column): (M + H) 444.3.

156 white solid. Cis isomer. HPLC(Column): (254 nm) 99%. LC/MS(Column):(M + H) 444.3. Cis-isomer

157 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)386.2.

158 white solid. HPLC(Column): (254 nm) 93%. LC/MS(Column): (M + H)493.2.

159 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)547.3.

160 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)519.3.

161 white solid. Racemic. Cis isome. HPLC(Column): (254 nm) 94%.LC/MS(Column): (M + H) 430.3.

162 white solid. Racemic. Trans isomer. HPLC(Column): (254 nm) 90%.LC/MS(Column): (M + H) 430.3.

163 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)400.2.

164 white solid. Racemic. Cis Isomer. HPLC(Column): (254 nm) 99%.LC/MS(Column): (M + H) 430.3.

165 white solid. Racemic. Trans isomer. HPLC(Column): (254 nm) 99%.LC/MS(Column): (M + H) 430.3.

166 white solid. Racemic. HPLC(Column): (254 nm) 93%. LC/MS(Column):(M + H) 416.2.

167 Racemic-HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H) 416.2.

168 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)519.3.

169 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)519.3.

170 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)479.2.

171 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)479.2.

172 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)509.25.

173 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)505.3.

174 white solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)493.25.

175 white solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)507.3.

176 white solid. Racemic. Cis isomer. HPLC(Column): (254 nm) 94%.LC/MS(Column): (M + H) 493.25.

177 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)481.3.

178 white solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)507.35.

179 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)467.3.

180 yellow solid. HPLC(Column): (254 nm) 89%. LC/MS(Column): (M + H)446.4.

181 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)416.2.

182 white solid. Trans isomer. HPLC(Column): (254 nm) 96%.LC/MS(Column): (M + H) 507.3.

183 white solid. Cis-isomer. HPLC(Column): (254 nm) 95%. LC/MS(Column):(M + H) 479.2.

184 Off White Solid. HPLC (Xbridge): (254 nm) 93.4%. LC/MS(Column): (M +H) 471.0. 1H NMR (DMSO-d6, 400 MHz): 9.07 (t, J = 5.9 Hz, 1H), 8.81 (s,1H), 8.55-8.55 (m, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.23 (s, 1H), 7.93 (s,1H), 7.73 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.33 (t, J =5.8 Hz, 1H), 3.89 (s, 4H), 2.91 (s, 3H), 2.81 (s, 3H), 2.49 (s, 3H).

185 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)415.25. 1H NMR (400 MHz, DMSO-d6) d 8.52 (d, J = 6.7 Hz, 1H), 8.21 (d, J= 2.0 Hz, 3H), 8.04 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.66 (d, J =7.6 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.21 (d, J = 6.9 Hz, 1H), 4.74(m, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.44 (m 1H), 2.23 (m, 1H), 1.88 (m,3H), 1.47 (m, 2H).

186 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)455.3. 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 8.17 (dd, J = 15.6, 9.5Hz, 3H), 8.07 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 7.7 Hz,1H), 7.51 (t, J = 7.7 Hz, 1H), 5.38 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H),2.19 (m, 6H), 1.63 (m, 6H), 1.31 (s, 2H).

187 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)533.3. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.24-8.04 (m, 4H), 7.87(s, 1H), 7.76 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz,1H), 6.94 (s, 1H), 5.44 (s, 1H), 3.92 (s, 6H), 2.97 (s, 3H), 2.29-2.17(m, 6H), 2.07-1.93 (m, 6H).

188 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)415.3. 1H NMR (400 MHz, DMSO-d6) d 8.51 (d, J = 10.8 Hz, 1H), 8.19 (m,3H), 8.06 (d, J = 9.3 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 4.5 Hz, 1H),7.66 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.60 (dd, J = 17.6,6.7 Hz, 1H), 4.68 (m, 0.3H), 4.55 (m, 0.7H), 3.93 (s, 3H), 3.88 (s, 3H),3.00 (m, 0.3H), 2.74 (m, 0.7H), 2.58 (d, J = 6.5 Hz, 1H), 2.47-2.40 (m,1H), 2.28-1.99 (m, 2.7H), 1.78 (m, 1.3H).

189 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)505.3. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.33 (s, 1H), 8.20 (d,J = 8.8 Hz, 2H), 8.10 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.66 (d, J =7.6 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 4.66(ddt, J = 10.7, 6.7, 3.3 Hz, 1H), 4.22 (s, 1H), 3.90 (s, 6H), 3.10 (d, J= 8.6 Hz, 1H), 2.97 (s, 3H), 2.65 (s, 1H), 2.35-2.27 (m, 1H), 2.09 (d, J= 5.5 Hz, 1H), 1.82 (d, J = 10.6 Hz, 1H), 1.72 (d, J = 10.8 Hz, 1H),1.19 (dt, J = 13.4, 3.2 Hz, 1H).

190 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)493.25. 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 8.21 (m, 3H), 8.04 (s,1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.19 (s, 1H), 6.39 (d, J = 6.9 Hz, 1H), 4.73 (m, 1H), 3.92(s, 3H), 3.85 (s, 3H), 3.84 (m, 1H)), 2.91 (s, 3H), 2.23 (m, 1H), 2.04(m, 3H), 1.61 (m, 2H).

191 off white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)427.3. 1H NMR (400 MHz, DMSO-d6) d 8.49 (d, J = 1.8 Hz, 1H), 8.23-8.14(m, 3H), 7.89 (d, J = 10.1 Hz, 2H), 7.67 (dt, J = 7.7, 1.4 Hz, 1H), 7.56(s, 1H), 7.47 (t, J = 7.7 Hz, 1H), 3.90 (d, J = 3.1 Hz, 6H), 3.61 (m 7m,2H), 3.24 (m, 2H), 2.88 (m, 2H), 2.71 (m, 2H), 2.59 (m, 2H).

192 white solid. HPLC(Column): (254 nm) 95.3%. LC/MS(Column): (M + H)497.0. 1H-NMR (400 MHz, DMSO-d6): 9.12 (t, J = 5.60 Hz, 1H), 8.82 (s,1H), 8.55 (s, 1H), 8.26 (d, J = 8.00 Hz, 1H), 8.22 (s, 1H), 7.92 (s,1H), 7.75 (d, J = 7.20 Hz, 1H), 7.52 (t, J = 7.60 Hz, 1H), 4.04 (t, J =6.40 Hz, 2H), 3.97 (t, J = 8.40 Hz, 2H), 3.90 (s, 3H), 3.81 (t, J = 6.00Hz, 2H), 3.07-3.12 (m, 1H), 2.98 (s, 3H).

193 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)427.3.

194 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)443.3. 1H NMR (400 MHz, DMSO-d6) d 8.49 (s, 1H), 8.25-8.13 (m, 3H), 8.05(d, J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.6 Hz,1H), 7.47 (t, J = 7.7 Hz, 1H), 5.95 (m, 1H), 4.34-4.22 (m, 1H), 3.93 (s,3H), 3.90 (s, 3H), 2.96 (t, J = 6.2 Hz, 1H), 1.86-1.34 (m, 10H)

Example 195 and 196: Cis and TransN-(3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclobutylmethyl)-methanesulfonamide

Methanesulfonyl chloride (0.07 ml; 0.93 mmol; 1.20 eq.) was added to asolution of(3-Aminomethyl-cyclobutyl)-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-aminehydrochloride (350 mg; 0.78 mmol; 1.00 eq.) and TEA (0.22 mL; 1.55 mmol;2.00 eq.) in DMF (3 mL). The reaction mixture was stirred at roomtemperature overnight. It was then concentrated under reduced pressureand purified by preparative HPLC (25-28% CH₃CN in 0.1% NH₄OH in H₂O) togive the tittle compounds as cis and trans isomers: First elutingisomer: Yellow solid (17 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=1.9Hz, 1H), 8.25-8.16 (m, 3H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H),7.67 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.17-7.06 (m, 1H), 6.66(d, J=6.5 Hz, 1H), 4.77 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.17 (t,J=6.7 Hz, 2H), 2.95 (s, 3H), 2.29 (m, 5H). LC/MS: 493.3 (M+H). Secondeluting isomer: white solid (17 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49(d, J=1.9 Hz, 1H), 8.25-8.16 (m, 3H), 8.05 (s, 1H), 7.89 (s, 1H), 7.75(s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.98 (brs, 1H),6.63 (d, J=6.9 Hz, 1H), 4.61 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.02(d, J=6.9 Hz, 2H), 2.89 (s, 3H), 2.31-2.14 (m, 1H), 1.90-1.79 (m, 2H).LC/MS: 493.3 (M+H).

Compounds below were prepared following similar routes and protocols:

Structure Example Analyticals

197 white solid. Trans isomer. HPLC: (254 nm) 99%. LC/MS(Column): (M +H) 401.3. 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 8.25-8.15 (m, 3H),8.06 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.47(t, J = 7.7 Hz, 1H), 6.55 (m, 1H), 4.77 (m, 1H), 3.92 (s, 3H), 3.90 (s,3H), 3.55 (s, 1H), 2.35 (m, 2H), 2.19-2.06 (m, 2H)

198 white solid. HPLC: (254 nm) 100%. LC/MS(Column): (M + H) 485.4. 1HNMR (400 MHz, DMSO-d6) d 8.49 (s, 1H), 8.25-8.13 (m, 3H), 8.06 (s, 1H),7.88-7.75 (m, 3H), 7.66 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H),6.01 (d, J = 7.0 Hz, 1H), 4.32-4.23 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H),3.07 (t, J = 6.4 Hz, 2H), 1.82 (s, 3H), 1.74-1.55 (m, 7H), 1.41 (m, 2H)

199 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)505.3. 1H NMR (400 MHz, DMSO-d6) d 8.53 (d, J = 1.8 Hz, 1H), 8.27-8.18(m, 3H), 8.05 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 7.7 Hz,1H), 7.46 (t, J = 7.8 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.77 (t, J =4.5 Hz, 1H), 4.52 (dd, J = 11.1, 5.2 Hz, 1H), 4.22 (t, J = 4.7 Hz, 1H),3.92 (s, 3H), 3.90 (s, 3H), 3.16 (s,, 3H), 2.32 (m, 1H), 1.85 (m, 2H),1.75-1.61 (m, 3H)

200 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)429.3

201 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)521.3. 1H NMR (400 MHz, DMSO-d6) d 8.49 (d, J = 1.8 Hz, 1H), 8.25-8.14(m, 3H), 8.06 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 7.8 Hz,1H), 7.47 (t, J = 7.7 Hz, 1H), 6.99 (s, 1H), 6.01 (d, J = 6.9 Hz, 1H),4.33-4.23 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.99-2.88 (m, 5H),1.84-1.59 (m, 7H), 1.48 (m, 2H)

202 yellow solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)443.3. 1H NMR (400 MHz, DMSO-d6) d 8.51 (d, J = 1.8 Hz, 1H), 8.33 (d, J= 7.0 Hz, 1H), 8.25-8.16 (m, 3H), 8.07 (s, 1H), 7.89 (s, 1H), 7.76 (s,1H), 7.67 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.75 (d, J =6.0 Hz, 1H), 4.78 (m, 1H), 4.25 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H),2.47 (d, J = 7.4 Hz, 2H), 2.33 (m, 2H), 1.86 (s, 3H).

203 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)507.3. 1H NMR (400 MHz, DMSO-d6) d 8.55-8.47 (m, 1H), 8.20 (m, 3H), 8.04(s, 1H), 7.91-7.85 (m, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.47(t, J = 7.8 Hz, 1H), 7.13 (t, J = 9.3 Hz, 1H), 6.65 (t, 6.0 Hz, 0.5H),6.55 (t, J = 6 Hz, 0.5H), 3.94 (s, 3H), 3.90 (s, 3H), 3.86-3.63 (m, 2H),3.51 (m, 2H), 2.97-2.83 (m, 3H), 2.31 (m, 1H), 2.05-1.36 (m, 6H).

205 Off white solid. HPLC(Column): (254 nm) 96.1%. LC/MS(Column): (M +H) 489.2. 1H-NMR (400 MHz, DMSO-d6): 9.27 (d, J = 6.80 Hz, 1H), 8.83 (s,1H), 8.54 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 7.20 Hz,1H), 7.90 (s, 1H), 7.75 (d, J = 7.60 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H),4.56-4.56 (m, 1H), 3.91 (s, 3H), 3.80-3.82 (m, 1H), 2.83 (s, 3H),1.91-1.95 (m, 4H), 1.83 (s, 3H), 1.74 (m, 2H), 1.60 (m, 2H).

Examples 206 and 207:N-[(Cis)-2-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-cyclopentyl]-acetamideandN-[(Trans)-2-({5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-methyl)-cyclopentyl]-acetamide

Acetyl chloride (0.01 ml; 0.13 mmol; 1.20 eq.) was added to a solutionof(2-Amino-cyclopentylmethyl)-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-aminehydrochloride (50 mg; 0.11 mmol; 1.00 eq.) and TEA (0.03 ml; 0.22 mmol;2.00 eq.) in DMF (2 mL). The reaction mixture was stirred at RTovernight. It was then concentrated under reduced pressure and purifiedby preparative HPLC (25-28% CH₃CN in 0.1% NH₄OH in H₂O) to give thetitle compounds as cis and trans isomers: First eluting isomer: Yellowsolid (15 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.20 (m, 3H),8.08 (s, 1H), 7.90 (m, 2H), 7.76 (s, 1H), 7.65 (m, 1H), 7.46 (t, J=7.7Hz, 1H), 6.73 (t, J=5.6 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.86 (m,1H), 3.69 (m, 1H), 3.43 (m, 1H), 2.11 (mz, 1H), 1.89 (m, 4H), 1.85 (s,3H), 1.62 (m 2H), 1.44 (m, 2H). LC/MS: 471.2 (M+H). Second elutingisomer: Yellow solid (11 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H),8.20 (m, 3H), 8.11 (s, 1H), 7.89 (s, 1H), 7.81 (m, 2H), 7.66 (d, J=7.6Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 6.75 (m, 1H), 4.22 (m, 1H), 3.92 (s,3H), 3.90 (s, 3H), 3.86 (m, 1H), 3.11 (m, 1H), 2.27 (m, 1H), 1.87 (s,3H), 1.81-1.71 (m, 3H), 1.60-1.49 (m, 2H), 1.41 (m, 1H). LC/MS: 471.2(M+H).

Example 208:(1S,2R,3S)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexane-1,2-diolStep 1:((3aR,4S,7aS)-2,2-Dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-amine

The title compound was obtained following the procedure described forexample 28 from2-[(3aR,4S,7aS)-2,2-dimethylhexahydro-1,3-benzodioxol-4-yl]-1H-isoindole-1,3(2H)-dione(prepared as described in WO 2010017051). LC/MS: 486.3 (M+H).

Step 2:(1S,2R,3S)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexane-1,2-diol

Hydrogen chloride (1.24 ml; 2.47 mmol; 5.00 eq.) (2.0 M solution inEt2O) was added to a solution of((3aR,4S,7aS)-2,2-Dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-amine(240 mg; 0.49 mmol; 1.00 eq.) in methanol (3.0 mL). The reaction mixturewas stirred at rt overnight. It was then concentrated under reducedpressure and purified using prep-HPLC (20-24% CH₃CN in 0.1% NH₄OH inH₂O) to give the title compound as a white solid (180 mg; 82%). 1H NMR(400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.24-8.14 (m, 3H), 8.07 (s, 1H), 7.86(s, 1H), 7.78 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H),6.06 (d, J=6.9 Hz, 1H), 4.73-4.35 (m, 3H), 3.92 (m, 7H), 3.59 (d, J=9.7Hz, 1H), 2.20-2.11 (m, 1H), 1.77 (m, 2H), 1.37 (m, 3H). LC/MS: 446.2(M+H).

Compounds below were prepared following similar routes and protocols:

Structure Example Analyticals

209 Off white solid. Pure trans isomer. HPLC(Column): (254 nm) 94.9%.LC/MS: (M + H) 551.0. 1H-NMR (400 MHz, CDCl3): 8.96 (d, J = 7.60 Hz,1H), 8.65 (s, 1H), 8.59 (t, J = 1.60 Hz, 1H), 8.30 (d, J = 5.20 Hz, 1H),7.89 (s, 1H), 7.74 (s, 1H), 7.62 (d, J = 1.60 Hz, 1H), 7.51 (t, J = 7.60Hz, 1H), 4.35-4.39 (m, 1H), 4.17 (d, J = 7.60 Hz, 1H), 4.00 (s, 3H),3.48-3.49 (m, 1H), 2.86 (s, 3H), 2.49- 2.49 (m, 1H), 2.34 (m, 2H), 2.28(m, 2H), 1.58 (m, 3H), 1.24 (m, 2H), 1.05 (m, 2H).

210 Off white solid. HPLC(Column): (254 nm): 93.4%. LC/MS: (M + H)461.2. 1H-NMR (400 MHz, DMSO-d6): 8.89 (s, 1H), 8.86 (s, 1H), 8.55-8.56(m, 3H), 8.25 (d, J = 8.00 Hz, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 7.75 (d,J = 7.60 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H), 4.62-4.65 (m, 1H), 3.91 (s,3H), 3.62-3.70 (m, 1H), 3.40 (m, 2H), 3.10 (t, J = 11.20 Hz, 2H), 2.29(d, J = 11.60 Hz, 1H), 1.98-2.01 (m, 2H), 1.37 (m, 6H).

Examples 211 and 212: Cis and TransN-(3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclobutylmethyl)-acetamide

The title compounds were obtained following the procedure described forexamples 208 and 209, from(3-Aminomethyl-cyclobutyl)-{5-(1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-aminehydrochloride (mixture of the two isomers). First eluting isomer: Whitesolid (47 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.24-8.15 (m,3H), 8.06 (s, 1H), 7.90 (m, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.67 (d,J=7.7 Hz, 1H), 7.47 (td, J=7.8, 2.0 Hz, 1H), 6.64 (d, J=6.6 Hz, 1H),4.79 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.28 (t, J=7.3 Hz, 2H),2.33-2.14 (m, 5H), 1.85 (s, 3H). LC/MS: 457.3 (M+H). Second elutingisomer: White solid (25 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),8.18-8.22 (m, 3H), 8.05 (2, 1H), 7.89 (s, 1H), 7.80 (m, 1H), 7.75 (s,1H), 7.66 (d, J=4 Hz, 1H, 7.48 (t, J=8 Hz, 1H), 6.60 (d, J=8 Hz, 1H),4.55 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.13 (m, 2H), 2.45 (m, 2H),2.17 (m, 1H), 1.85 (m, 1H), 1.77 (s, 3H). LC/MS: 457.3 (M+H).

Compounds below were prepared following similar routes and protocols:

Structure Example Analyticals

213 white solid. HPLC: (254 nm) 97%. LC/MS: (M + H) 452.2. 1H NMR (400MHz, DMSO-d6) d 8.50 (d, J = 2.1 Hz, 1H), 8.25-8.17 (m, 3H), 8.08-8.02(m, 1H), 7.90 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 7.7 Hz,1H), 7.50-7.43 (m, 1H), 6.82 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H), 3.89 (s,3H), 3.67 (m, 2H), 3.24 (t, J = 7.9 Hz, 2H), 3.07 (s, 3H), 2.13 (m, 2H).

214 Yellow solid. HPLC: (254 nm) 92.6%. LC/MS: (M + H) 468.0. 1H-NMR(400 MHz, DMSO-d6): 9.01 (d, J = 7.20 Hz, 1H), 8.84 (s, 1H), 8.57 (t, J= 1.60 Hz, 1H), 8.27 (d, J = 7.60 Hz, 1H), 8.22 (s, 1H), 7.92 (s, 1H),7.74 (d, J = 800 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H), 4.51-4.53 (m, 1H),3.91 (s, 3H), 2.82 (s, 3H), 2.11-2.22 (m, 6H), 1.76- 1.79 (m, 2H).

215 White solid. HPLC: (254 nm) 95.6%. LC/MS: (M + H) 504.2. 1H NMR (400MHz, DMSO-d6): ppm 8.56-8.51 (m, 2H), 8.21-8.19 (m, 2H), 8.13 (s, 1H),7.90 (s, 1H), 7.81-7.78 (m, 1H), 7.70-7.68 (m, 1H), 7.50-7.46 (m, 1H),7.40-7.38 (m, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.33- 4.29 (m, 1H), 3.89(s, 3H), 3.63-3.60 (m, 2H), 2.98-2.91 (m, 5H), 2.55 (s, 3H), 2.04-2.01(m, 2H), 1.72-1.63 (m, 2H).

216 Pale Yellow Solid. HPLC: (254 nm) 95.7%. LC/MS: (M + H) 462.0.

217 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)430.3. 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 8.23-8.13 (m, 3H), 8.02(s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.48 (t,J = 7.7 Hz, 1H), 7.40 (m, 1H), 6.76 (t, J = 5.9 Hz, 1H), 3.95-3.81 (m,7H), 3.73 (d, J = 11.2 Hz, 1H), 3.47- 3.35 (m, 3H), 3.23 (t, J = 10.2Hz, 1H), 2.12-2.02 (m, 1H), 1.90-1.82 (m, 1H), 1.68-1.60 (m, 1H), 1.54-1.28 (m, 2H).

218 white solid. HPLC(Column): (254 nm) 90.5%. LC/MS(Column): (M + H)402.2. 1H NMR (400 MHz, DMSO-d6) d 8.53-8.47 (m, 1H), 8.22-8.11 (m, 3H),7.86 (d, J = 22.3 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.53- 7.44 (m, 2H),4.90 (s, 1H), 4.28 (d, J = 4.8 Hz, 1H), 3.90 (d, J = 1.8 Hz, 6H), 3.58(q, J = 9.4, 8.7 Hz, 1H), 3.52- 3.42 (m, 2H), 3.16 (d, J = 11.8 Hz, 1H),1.96-1.78 (m, 2H).

219 hite solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)416.25. 1H NMR (400 MHz, DMSO-d6) d 8.46 (d, J = 24.2 Hz, 2H), 8.23-8.15(m, 2H), 8.06 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.7 Hz,1H), 7.48 (t, J = 7.8 Hz, 1H), 4.71 (s, 1H), 3.91 (d, J = 6.6 Hz, 6H),3.80-3.67 (m, 3H), 3.06 (t, J = 11.5 Hz, 2H), 1.87-1.75 (m, 2H), 1.47(m, 2H).

220 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)430.3.

221 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)430.3. 1H NMR (400 MHz, DMSO-d6) d 8.50 (d, J = 2.0 Hz, 1H), 8.24-8.14(m, 3H), 8.07 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.75 (d, J= 1.8 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47 (td, J = 7.8, 1.9 Hz, 1H),5.98 (d, J = 7.0 Hz, 1H), 4.45- 4.38 (m, 1H), 4.17 (d, J = 10.6 Hz, 1H),3.91 (m, 6H), 3.82-3.76 (m, 1H), 1.87 (m, 2H), 1.77-1.60 (m, 6H).

222 white solid. HPLC: (254 nm) 93%. LC/MS: (M + H) 399.3.. 1H NMR (400MHz, DMSO-d6) d 8.50 (s, 1H), 8.34 (s, 1H), 8.23-8.17 (m, 2H), 7.93 (d,J = 14.0 Hz, 2H), 7.71-7.64 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 3.90 (d,J = 8.0 Hz, 8H), 2.94 (t, J = 6.8 Hz, 2H), 2.86 (s, 3H).

223 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)388.3. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.22-8.06 (m, 4H), 7.85(s, 1H), 7.78 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.7 Hz,1H), 5.57 (s, 1H), 3.91 (d, J = 9.6 Hz, 6H), 1.56 (s, 9H).

224 hite solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)444.3. 1H NMR (400 MHz, DMSO-d6) d 8.55 (s, 1H), 8.26-8.15 (m, 3H), 8.02(d, J = 1.9 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H),7.65 (d, J = 7.7 Hz, 1H), 7.46 (td, J = 7.8, 2.0 Hz, 1H), 6.92 (t, J =5.4 Hz, 1H), 5.09 (s, 1H), 3.912 (2, 3H), 3.89 (s, 3H), 3.61 (m, 2H),3.26 (dd, J = 10.7, 4.8 Hz, 1H), 1.91-1.75 (m, 2H), 1.69-1.57 (m, 3H),1.26- 1.02 (m, 4H).

225 white solid. HPLC(Column): (254 nm) 88%. LC/MS(Column): (M + H)444.2. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.17 (m, 3H), 8.02 (s,1H), 7.87 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 6.78-6.70 (m, 1H), 4.57 (s, 1H), 3.92 (2, 3H), 3.89 (s,3H), 3.86 (s, 1H), 3.52 (t, J = 6.3 Hz, 2H), 1.93-1.83 (m, 1H),1.74-1.32 (m, 7H), 1.28- 1.17 (m, 1H).

226 off-white solid. HPLC(Column): (254 nm) 93%. LC/MS(Column): (M + H)388.1. 1H NMR (400 MHz, DMSO-d6) d 8.49 (s, 1H), 8.22-8.16 (m, 3H),7.90- 7.86 (m, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H),7.50-7.45 (m, 1H), 5.60 (s, 1H), 4.46 (m, 1H), 4.15 (t, J = 8.2 Hz, 2H),3.93 (s, 3), 3.86 (s, 3H), 3.70 (dd, J = 9.8, 4.3 Hz, 2H).

227 off-white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)444.2. 1H NMR (400 MHz, DMSO-d6) d 8.53 (s, 1H), 8.23-8.16 (m, 3H), 8.03(s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.45 (dd,J = 8.5, 6.8 Hz, 1H), 6.86 (t, J = 5.5 Hz, 1H), 4.44 (s, 1H), 3.91 (2,3H), 3.88 (s, 3H), 3.70 (m, 2H), 1.88 (m, 2H), 1.69 (m, 4H), 1.56 (m,4H).

228 off-white solid. HPLC: (254 nm) 97.7%. LC/MS: (M + H) 430.2. 1H NMR(400 MHz, DMSO-d6) 8.50 (s, 1H), 8.19 (d, J = 8.2 Hz, 2H), 8.12 (d, J =1.9 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.66(d, J = 7.6 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.47 (td, J = 7.8, 1.8Hz, 1H), 4.45 (s, 1H), 3.91 (s, 3H), 3.89 (2, 3H), 3.58- 3.52 (m, 1H),3.41 (dt, J = 21.5, 7.9 Hz, 4H), 3.04 (t, J = 9.8 Hz, 1H), 2.20 (m, 1H),2.00 (m, 1H), 1.55-1.43 (m, 3H).

229 hite solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)447.2. 1H NMR (400 MHz, DMSO-d6): 8.50 (s, 1H), 8.23-8.14 (m, 3H), 8.03(s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47 (t,J = 7.8 Hz, 1H), 6.77 (t, J = 5.8 Hz, 1H), 4.68 (d, J = 48 Hz, 1), 3.92(2, 3H), 3.89 (s, 3H), 3.63 (dt, J = 13.4, 6.5 Hz, 1H), 3.47 (dt, J =12.8, 6.2 Hz, 1H), 3.10 (t, J = 12.9 Hz, 1H), 2.95 (d, J = 13.0 Hz, 1H),2.71-2.56 (m, 1H), 2.44 (d, J = 12.3 Hz, 1H), 2.24-2.06 (m, 1H), 1.91(s, 1H), 1.54-1.39 (m, 2H).

230 hite solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)416.2. 1H NMR (400 MHz, DMSO-d6) 8.52 (s, 1H), 8.22-8.15 (m, 3H), 7.90(s, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.55 (s,1H), 7.47 (t, J = 7.7 Hz, 1H), 4.75 (s, 1H), 4.53 (m, 1H), 3.90 (s, 3H),3.88 (s, 3H), 3.79-3.73 (m, 1H), 3.57 (dd, J = 10.6, 6.6 Hz, 1H),3.20-3.13 (m, 1H), 2.97 (m, 1H), 1.91 (m, 3H), 1.72-1.60 (m, 1H).

231 off-white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)447.2. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.26-8.16 (m, 3H), 8.05(s, 1H), 7.89 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 7.7 Hz,1H), 7.48 (dd, J = 8.5, 6.9 Hz, 1H), 6.59-6.50 (m, 1H), 3.93 (s, 3H),3.88 (s, 3H), 3.84 (m, 2H), 2.83- 2.65 (m, 4H), 1.77-1.58 (m, 4H).

232 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)472.2. 1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1H), 8.24-8.14 (m, 3H), 8.05(s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.47 (t,J = 8.0 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 4.26- 4.16 (m, 1H), 3.91 (s,3H), 3.89 (s, 3H), 3.60 (s, 3H), 2.62 (m, 1H), 2.28 (m, 1H), 2.04-1.81(m, 3H), 1.61- 1.22 (m, 5H).

233 brown solid. HPLC(Column): (254 nm) 93%. LC/MS(Column): (M + H)499.2.

234 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)525.2.

235 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)489.2.

236 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)525.2. 1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1H), 8.27-8.16 (m, 3H), 8.05(d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H),7.67 (d, J = 7.7 Hz, 1H), 7.51-7.45 (m, 1H), 6.68 (t, J = 6.4 Hz, 1H),3.96-3.85 (m, 8H), 3.50 (m, 2H), 2.98-2.85 (m, 5H), 2.00-1.80 (m, 4H).

237 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)489.2.

238 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)416.2. 1H NMR (400 MHz, DMSO-d6) 8.54 (d, J = 1.8 Hz, 1H), 8.24-8.16 (m,3H), 8.06 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.66 (d, J =7.7 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.21 (d, J = 6.6 Hz, 1H), 4.87(s, 1H), 4.29 (m, 1H), 4.13 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.25(m, 1H), 1.90 (m, 1H), 1.70 (m, 2H), 1.56 (m, 2H).

239 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)415.2. 1H NMR (400 MHz, DMSO-d6) 8.49 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H),8.19 (m, 2H), 8.05 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 7.7Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 3.91 (m, 8H), 2.90 (m, 2H), 2.82-2.73(m, 1H), 1.75 (d, J = 12.0 Hz, 2H), 1.32 (m, 2H).

240 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)445.2. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.19 (m, 3H), 8.07 (s,1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.48 (t, J =7.7 Hz, 1H), 6.28 (t, J = 6.0 Hz, 1H), 4.70 (s, 1H), 3.92 (s, 3H), 3.89(s, 3H), 3.63 (d, J = 5.7 Hz, 2H), 2.85-2.60 (m, 4H), 1.54-1.39 (m, 4H).

241 white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)401.15.

242 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)427.2. 1H NMR (400 MHz, DMSO-d6) 8.56 (d, J = 15.5 Hz, 1H), 8.25-8.12(m, 3H), 8.00 (s, 1H), 7.87 (s, 1H), 7.68 (m, 2H), 7.49 (t, J = 7.7 Hz,1H), 7.05 (s, 1H), 3.95-3.86 (m, 6H), 2.77 (s, 2H), 2.11 (s, 6H).

243 Off white solid. HPLC: (254 nm) 94.6%. LC/MS: (M + H) 482.2. 1H-NMR(400 MHz, DMSO-d6): 8.99 (d, J = 7.20 Hz, 1H), 8.85 (s, 1H), 8.58 (s,1H), 8.31 (d, J = 8.00 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.75 (d, J =7.60 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H), 4.68-4.69 (m, 1H), 3.91 (s,3H), 3.51-3.57 (m, 2H), 3.17-3.21 (m, 2H), 2.82 (s, 3H), 2.50-2.50 (m,2H).

244 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)430.2. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.24-8.14 (m, 3H), 8.09(s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.49 (t,J = 7.9 Hz, 1H), 6.11 (d, J = 6.5 Hz, 1H), 4.86- 4.78 (m, 1H), 3.92 (m,7H), 3.64-3.52 (m, 1H), 2.30- 2.20 (m, 1H), 2.00-1.91 (m, 1H), 1.77-1.67(m, 2H), 1.44-1.23 (m, 4H).

245 white solid. HPLC(Column): (254 nm) 86%. LC/MS(Column): (M + H)505.2. 1H NMR (400 MHz, DMSO-d6) 8.52 (s, 1H), 8.24-8.14 (m, 3H), 8.01(d, J = 2.2 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.71-7.67 (m, 2H),7.53-7.48 (m, 1H), 7.08 (t, J = 6.3 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H),3.25-3.22 (m, 2H), 2.95-2.89 (m, 3H), 2.17 (d, J = 2.1 Hz, 6H).

246 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)443.2. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.23-8.14 (m, 3H), 8.07(d, J = 6.8 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H),7.67 (d, J = 7.7 Hz, 1H), 7.55 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 4.24(m, 1H), 3.91 (s, 3H), 3.89 (2, 3H), 3.51 (m, 3H), 3.23-3.17 (m, 1H),2.03 (m, 1H), 1.80 (s, 3H), 1.77 (s, 1H).

247 white solid. HPLC(Column): (254 nm) 97%. LC/MS(Column): (M + H)479.1. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.23-8.16 (m, 3H), 7.88(dd, J = 15.1, 2.1 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 2.1Hz, 1H), 7.48 (td, J = 7.8, 2.0 Hz, 1H), 7.37 (s, 1H), 3.90 (m, 7H),3.62 (m, 1H), 3.54 (m, 1H), 3.43 (m, 1H), 2.95 (s, 3H), 2.17-2.09 (m,1H), 1.89 (m, 1H).

248 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)460.2.

249 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)523.2

250 white solid. HPLC(Column): (254 nm) 89%. LC/MS: (M + H) 493.2. 1HNMR (400 MHz, DMSO-d6) 8.52- 8.44 (m, 2H), 8.24-8.16 (m, 2H), 8.09-8.04(m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.81-7.75 (m, 1H), 7.68 (d, J = 7.7Hz, 1H), 7.53-7.46 (m, 1H), 3.95-3.86 (m, 8H), 3.42 (m, 7.9 Hz, 1H),3.05-2.91 (m, 5H), 1.91 (m, 2H), 1.55 (m, 2H).

251 white solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)443.2.

252 white solid. HPLC: (254 nm) 97%. LC/MS: (M + H) 443.2. 1H NMR (400MHz, DMSO-d6) 8.52 (s, 1H), 8.20 (m, 3H), 8.08 (d, J = 2.0 Hz, 1H),7.90-7.85 (m, 1H), 7.81- 7.76 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.48(tt, J = 7.6, 1.5 Hz, 1H), 6.48 (d, J = 5.7 Hz, 1H), 3.96 (s, 3H), 3.87(s, 3H), 3.55-3.47 (m, 2H), 1.62-1.28 (m, 12H).

253 Off white solid. HPLC: (254 nm) 98.1%. LC/MS: (M + H) 525.3. 1H-NMR(400 MHz, DMSO-d6): 9.06 (d, J = 7.20 Hz, 1H), 8.83 (s, 1H), 8.55 (s,1H), 8.26 (d, J = 7.60 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.75 (d, J =8.00 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H), 4.56-4.56 (m, 1H), 3.91 (s,3H), 3.47-3.48 (m, 3H), 3.36-3.46 (m, 1H), 2.96 (s, 3H), 2.82 (s, 3H),2.27-2.28 (m, 1H), 2.10-2.12 (m, 1H), 1.89-1.91 (m, 4H).

254 Off white solid. HPLC: (254 nm) 96.7%. LC/MS: (M + H) 525.0. 1H-NMR(400 MHz, Acetone): 9.10 (d, J = 7.60 Hz, 1H), 8.76 (s, 1H), 8.70 (t, J= 1.60 Hz, 1H), 8.34 (d, J = 5.20 Hz, 1H), 8.07 (s, 1H), 7.88 (s, 1H),7.74 (d, J = 5.20 Hz, 1H), 7.51 (t, J = 8.00 Hz, 1H), 4.38-4.39 (m, 1H),3.98 (s, 3H), 3.80 (s, 1H), 3.45-3.46 (m, 1H), 3.10 (m, 1H), 3.00 (s,3H), 2.38 (m, 2H), 2.24 (m, 2 H), 2.08 (s, 3H), 1.63-1.74 (m, 4H).

255 white solid. HPLC(Column): (254 nm) 94%. LC/MS(Column): (M + H)457.2. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.26-8.15 (m, 3H), 8.05(s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.47 (t,J = 7.9 Hz, 1H), 6.27 (dd, J = 20.1, 7.5 Hz, 1H), 4.39 (m, 2H), 3.91 (m,7H), 3.25 (m 1H), 2.84 (m, 1H), 2.12-1.84 (m, 5H), 1.71-1.47 (m, 2H).

256 yellow solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)485.2. 1H NMR (400 MHz, DMSO-d6) d 8.59 (s, 1H), 8.32 (s, 1H), 8.21 (q,J = 3.5 Hz, 2H), 8.06 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.66 (d, J =7.7 Hz, 1H), 7.48-7.38 (m, 2H), 6.64 (d, J = 6.4 Hz, 1H), 3.91 (m, 8H),2.17-2.09 (m, 2H), 1.82 (s, 3H), 1.57-1.39 (m, 7H), 1.26 (m, 1H).

257 White solid. HPLC: (254 nm) 99.5%. LC/MS: (M + H) 464.2. 1H NMR (400MHz, DMSO-d6): 8.51 (s, 1H), 8.26-8.22 (m, 3H), 8.07 (s, 1H), 7.94 (s,1H), 7.76 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H),6.55 (d, J = 7.6 Hz, 1H), 4.55-4.54 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H),3.50-3.42 (m, 2H), 3.17-3.14 (m, 2H), 2.26-2.23 (m, 4H).

258 light brown solid. HPLC(Column): (254 nm) 86%. LC/MS(Column): (M +H) 485.2.

259 white solid. HPLC(Column): (254 nm) 92%. LC/MS(Column): (M + H)521.1. 1H NMR (400 MHz, DMSO-d6) d 8.50 (s, 1H), 8.25-8.16 (m, 3H),8.07- 8.02 (m, 1H), 7.92-7.86 (m, 1H), 7.78-7.71 (m, 1H), 7.66 (d, J =7.7 Hz, 1H), 7.46 (ddd, J = 9.2, 5.2, 1.8 Hz, 1H), 6.64 (d, J = 6.1 Hz,1H), 4.06-3.97 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.75-3.56 (m, 2H),3.45 (m, 1H), 3.11-2.92 (m, 4H), 2.14-2.03 (m, 1H), 1.86 (m, 1H),1.73-1.38 (m, 6H).

260 light yellow solid. HPLC(Column): (254 nm) 97.7%.

261 white solid. HPLC: (254 nm) 99%. LC/MS: (M + H) 416.2. 1H NMR (400MHz, DMSO-d6) 8.49 (s, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 1.8Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.84 (s, 1H), 7.66 (d, J = 7.7 Hz,1H), 7.53 (d, J = 1.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 4.66 (s, 1H),3.90 (s, 3H), 3.89 (s, 3H), 3.54-3.20 (m, 6H), 2.28 (m, 1H), 1.92 (m,1H), 1.65 (m, 1H).

262 white solid. HPLC: (254 nm) 94%. LC/MS: (M + H) 521.1. 1H NMR (400MHz, DMSO-d6) d 8.54 (s, 1H), 8.28- 8.24 (m, 1H), 8.20 (m, 2H), 8.11 (d,J = 2.0 Hz, 1H), 7.91- 7.87 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.66 (d,J = 7.7 Hz, 1H), 7.50-7.44 (m, 1H), 6.95 (s, 1H), 6.30 (t, J = 6.3 Hz,1H), 3.97-3.88 (m, 8H), 3.06-3.02 (m, 3H), 1.86 (t, J = 8.4 Hz, 2H),1.59 (m, 6H), 1.47-1.34 (m, 2H).

263 brown solid HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)499.2.

264 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)415.2.

265 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)493.1. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.24-8.10 (m, 3H), 7.90(s, 1H), 7.83 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.55-7.43 (m, 2H), 7.15(s, 1H), 3.90 (brs, 6H), 3.55 (m, 1H), 3.39 m, 2H), 3.23 (m, 1H), 2.99(m, 2H), 2.89 (d, J = 2.2 Hz, 3H), 2.33 (m, 1H), 1.97 (m, 1H), 1.65 (m,1H).

266 white solid. HPLC(Column): (254 nm) 91%. LC/MS(Column): (M + H)455.2. 1H NMR (400 MHz, DMSO-d6) 8.58 (d, J = 11.9 Hz, 2H), 8.35 (s,1H), 8.25- 8.15 (m, 2H), 8.00 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 8.4Hz, 2H), 7.48 (t, J = 7.9 Hz, 1H), 7.16 (s, 1H), 3.99 (s, 3H), 3.87 (s,3H), 2.49-2.37 (m, 6H), 1.85 (d, J = 2.1 Hz, 3H).

267 off-white solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)453.1. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.26-8.17 (m, 3H), 8.06(s, 1H), 7.94-7.88 (m, 1H), 7.79-7.73 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H),3.29-3.23 (m, 2H), 7.49-7.43 (m, 1H), 7.24 (s, 1H), 6.74 (d, J = 6.1 Hz,1H), 3.94-3.86 (m, 6H), 3.68 (m, 2H), 2.92-2.88 (m, 3H).

268 white solid HPLC(Column): (254 nm) 86%. LC/MS(Column): (M + H)446.1.

269 white solid. HPLC(Column): (254 nm) 81%. LC/MS(Column): (M + H)413.1.

270 white solid. HPLC(Column): (254 nm) 87%. LC/MS(Column): (M + H)491.1.

271 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)414.1. 1H NMR (400 MHz, DMSO-d6) 8.52 (d, J = 2.1 Hz, 1H), 8.38-8.31 (m,1H), 8.23-8.16 (m, 2H), 8.06-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.79-7.72(m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.49 (m, 1H), 7.21-7.11 (m, 1H),4.44-4.31 (m, 2H), 3.94 (s, 3H), 3.90 (s, 3H).

272 white solid. HPLC(Column): (254 nm) 100%. LC/MS(Column): (M + H)514.

273 white solid. HPLC(Column): (254 nm) 98%. LC/MS(Column): (M + H)432.1.

274 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)521.1. 1H NMR (400 MHz, DMSO-d6) 8.48 (s, 1H), 8.18 (m, 3H), 8.02 (d, J= 2.0 Hz, 1H), 7.90-7.84 (m, 1H), 7.75-7.70 (m, 1H), 7.66 (d, J = 7.8Hz, 1H), 7.48 (m, 1H), 6.20-6.14 (m, 1H), 4.41 (m, 1H), 3.94 (s, 3H),3.90 (s, 3H), 3.61 (t, J = 11.0 Hz, 2H), 2.83 (s, 3H), 2.69-2.59 (m,2H), 1.83 (m, 3H), 1.41-1.22 (m, 5H).

275 white solid. HPLC(Column): (254 nm) 96%. LC/MS(Column): (M + H)444.1. 1H NMR (400 MHz, DMSO-d6) 8.51 (s, 1H), 8.32-8.26 (m, 1H), 8.18(m, 2H), 8.07 (s, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.67 (m, 1H),7.51-7.44 (m, 1H), 6.82 (brs, 1H), 6.49 (brs, 1H), 4.52-4.42 (m, 1H),4.02 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.55 (m, 1H).

276 yellow solid. HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H)533.1. 1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1H), 8.25-8.13 (m, 3H), 8.03(s, 1H), 7.86 (s, 1H), 7.76-7.72 (m, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.49(m, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.17- 6.10 (m, 1H), 4.09 (d, J = 8.6Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.16 (m, 1H), 2.62-2.55 (m, 1H),2.04 (m, 4H), 1.50 (m, 4H), 1.01-0.87 (m, 4H).

277 white solid. HPLC(Column): (254 nm) 95%. LC/MS(Column): (M + H)487.2. 1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1H), 8.30-8.02 (m, 4H), 7.89(s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz,1H), 6.42 (m, 1H), 5.01 (s, 1H), 4.14-3.82 (m, 7H), 3.73-3.56 (m, 3H),3.01 (t, J = 11.2 Hz, 1H), 1.97 (s, 3H), 1.64-1.43 (m, 4H).

278 white solid. HPLC(Column): (254 nm) 99.2%. LC/MS(Column): (M + H)439.3. 1H NMR (400 MHz, DMSO-d6): 8.56 (s, 1H), 8.27 (s, 1H), 8.24-8.21(m, 2H), 8.06 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.0 Hz,1H), 7.46 (t, J = 7.6 Hz, 1H), 7.04 (s, 2H), 6.91 (t, J = 6.0 Hz, 1H),3.99-3.94 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.40 (t, J = 7.60 Hz,2H).

279 Off white solid. HPLC(Column): (254 nm) 98.4%. LC/MS(Column): (M +H) 458.0. 400 MHz, DMSO-d6): 8.49 (s, 1H), 8.20 (d, J = 4.8 Hz, 2H),8.16 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.66(d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 5.79 (d, J = 6.8 Hz, 1H),4.21-4.19 (m, 1H), 3.93-3.90 (m, 6H), 2.00 (s, 1H), 1.87-1.85 (m, 2H),1.75-1.71 (m, 4H), 1.58- 1.53 (m, 2H).

280 HPLC(Column): (254 nm) 99%. LC/MS(Column): (M + H) 434.4.

282 White solid. HPLC(Column): (254 nm) 97.8%. LC/MS(Column): (M + H)451.2. 1H NMR (400 MHz, DMSO-d6): 8.49 (t, J = 1.6 Hz, 1H), 8.24-8.18(m, 3H), 8.06 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.67-7.65 (m, 1H),7.46 (t, J = 8.0 Hz, 1H), 6.75 (t, J = 127.6 Hz, 1H), 3.93 (s, 3H), 3.90(s, 3H), 3.69-3.64 (m, 3H), 3.29 (s, 1H), 3.16 (t, J = 6.80 Hz, 2H),2.91 (s, 3H), 2.70 (s, 1H), 2.20-2.11 (m, 3H), 1.93-1.89 (m, 1H).

Example 281:(1R,2S,6S)-2-Methylamino-6-{5-(1-methyl-1-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexanol(Racemic—Relative Configuration) Step 1: tert-butylN-[(1S,2S,3S)-2-hydroxy-3-{[5-(1-methyl-H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino}cyclohexyl]-N-methylcarbamate(Racemic Relative Configuration)

A mixture of tert-butylN-[(1S,2S,3S)-3-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-2-hydroxycyclohexyl]-N-methylcarbamate(Intermediate 40, racemic, relative configuration, 420 mg, 0.87 mmol,1.00 equiv, 90%),1-methyl-4-[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole(440 mg, 1.30 mmol, 1.50 equiv, 84%), Pd(PPh3)2Cl2 (62 mg, 0.09 mmol,0.10 equiv, 98%) and potassium carbonate (245 mg, 1.74 mmol, 2.01 equiv,98%) in dioxane (10 mL) and water (1 mL) was degassed with nitrogen andheated in MW at 150° C. for 30 min. The resulting mixture wasconcentrated under vacuum and purified by flash chromatography on silica(MeOH/DCM, 1:5) to afford the title compound as a yellow solid (390 mg,73%). LC/MS (Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 um; Mobile PhaseA: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0mL/min; Gradient: 5% B to 100% B in 3.6 min, hold 1.0 min; 254 nm):(purity) 90%; [M+H]+ Cac. 559.3; found 559.3.

Step 2:(1R,2S,6S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino}-6-(methylamino)cyclohexan-1-o(Racemic Relative Configuration)

A solution of tert-butylN-[(1S,2S,3S)-2-hydroxy-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexyl]-N-methylcarbamate(50 mg, 0.08 mmol, 1.00 equiv, 90%) and conc.HCl (0.5 mL, 6.01 mmol, 74eq., 36.5%) in MeOH (2 mL) was stirred for 2 h at 25° C. The pH value ofthe solution was adjusted to 7 with sodium bicarbonate and the resultingmixture was concentrated under vacuum. The residue was dissolved in 10mL of DCM, the solids were filtered out and the resulting mixture wasconcentrated under vacuum. Purification of the crude (25 mg) by HPLCafforded the title compound as yellow solid (5 mg, 15%). m.p.: 88-92° C.LC/MS (Column: Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min;Gradient: 5% B to 100% B in 2.1 min, hold 0.5 min; 220 nm): (purity)98%; [M+H]+ Cac. 459.3; found 459.3. 1H NMR (300 MHz, DMSO-d6, ppm) δ8.52 (t, J=1.7 Hz, 1H), 8.24-8.12 (m, 3H), 8.06 (s, 1H), 7.89 (s, 1H),7.75 (s, 1H), 7.71-7.60 (m, 1H), 7.47 (t, J=7.7 Hz, 1H), 5.84 (d, J=7.7Hz, 1H), 5.07 (d, J=4.4 Hz, 1H), 4.55 (s, 1H), 3.93 (s, 3H), 3.89 (s,3H), 3.75 (q, J=3.9 Hz, 1H), 2.60 (d, J=3.8 Hz, 1H), 2.33 (s, 3H), 1.69(m, 5H), 1.41 (m, 2H).

Example 283 and 284:(R)-5,5-Difluoro-1-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylamineand(S)-5,5-Difluoro-1-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-yl}-piperidin-3-ylamineStep 1: tert-butylN-{5,5-difluoro-1-[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]piperidin-3-yl}carbamate

The title compound was obtained following the procedure described forexample 281, step 1 from tert-butylN-[1-[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-5,5-difluoropiperidin-3-yl]carbamate(Intermediate 42, 220 mg, 0.46 mmol, 1.00 eq.) as a white solid (135 mg,44%). LC/MS (Column: Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile PhaseA: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 100% B in 2.1 min, hold 0.5 min; 220 nm):(purity) 83.7%; [M+H]+ Cac. 551.4; found 551.4.

Step 2: (3R) and(3S)-5,5-difluoro-1-[5-(1-methyl-H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]piperidin-3-amine

Trifluoroacetic acid (1 mL, 13.46 mmol, 70.85 equiv) was added dropwiseto a solution of tert-butylN-[5,5-difluoro-1-[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]piperidin-3-yl]carbamate(125 mg, 0.19 mmol, 1.00 eq.) in dichloromethane (4 mL) maintained at 0°C. The resulting solution was stirred for 2 h at 25° C. It was thenconcentrated under vacuum and purified by Prep-HPLC (XBridge C18) toafford the title compound as a racemic mixture (30 mg). The twoenantiomers were then separated by chiral prep-HPLC (Lux 5u Cellulose-4,AXIA Packed, 100.0% MeOH, 0.1% DEA).

First eluting enantiomer: white solid (14.4 mg, 16%). M.p.: 70-73° C.LC/MS (Column: Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min;Gradient: 5% B to 100% B in 2.1 min, hold 0.5 min; 220 nm): (purity)97.5%; [M+H]+ Cac. 451.3; found 451.3. 1H NMR (400 MHz, DMSO, ppm): 8.49(m, 2H), 8.21-8.18 (m, 2H), 8.03 (s, 1H), 7.90 (s, 1H), 7.73 (s, 1H),7.68-7.66 (m, 1H), 7.49-7.45 (m, 1H), 4.10-4.08 (m, 1H), 3.94-3.85 (m,7H), 3.35 (s, 1H), 3.30-3.17 (m, 1H), 2.69-2.63 (m, 1H), 2.49-2.47 (m,1H), 2.31 (m, 1H), 1.83-1.72 (m, 1H).

Second elution enantiomer: white solid (15 mg, 17%). LC/MS (Column:Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to100% B in 2.1 min, hold 0.5 min; 220 nm): (purity) 97.8%; [M+H]+ Cac.451.3; found 451.3.

Example 285 and 286:(1S,2S,6S)-2-Fluoro-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexanoland(1R,2R,6R)-2-Fluoro-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexanol

The racemic mixture of the title compounds was obtained following theprocedure described for example 287 from(1S,2S,6S)-2-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-6-fluorocyclohexan-1-ol(Intermediate 45, relative stereochemistry, racemic, 360 mg, 0.99 mmol,1.00 eq.) Purification was performed by prep-HPLC [SHIMADZU: Column:XBridge BEH130 Prep C18 OBD Column, 19×150 mm, 5 μm, 13 nm; Mobilephase: water (10 mmol/L NH₄HCO₃) and ethanol (55% to 67% in 12 min);Detector: UV 254 nm] and the title compound was obtained as a whitesolid (200 mg, 43%). m.p: 176-180° C. HPLC (UV 254 nm): 94.57% purity.MS: m/z=448.2 [M+H]; ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.51 (s, 1H),8.26 (s, 1H), 8.17-8.14 (m, 2H), 8.07 (s, 1H), 7.86 (s, 1H), 7.77 (s,1H), 7.67-7.65 (m, 1H), 7.50-7.44 (m, 1H), 5.91 (d, J=7.8 Hz, 1H), 5.55(d, J=4.8 Hz, 1H), 4.87-4.65 (m, 1H), 4.52-4.42 (m, 1H), 4.07-4.02 (m,1H), 3.93 (s, 3H), 3.88 (s, 3H), 1.85-1.55 (m, 6H).

This racemic mixture was resolved by chiral-prep-HPLC [Column: RepairedChiral ADH, 21.2×250 mm, 5 μm; Mobile phase: hexane and ethanol (hold30% ethanol in 25 min); Detector: UV 254/220 nm].

First eluting enantiomer:(1S,2S,6S)-2-fluoro-6-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexan-1-ol(assumed stereochemistry): white solid (40 mg). m.p: 144-148° C. HPLC(UV 254 nm): 98.26% purity. Chiral purity: e.e. %>99.99%.

Second eluting enantiomer:(1R,2R,6R)-2-fluoro-6-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexan-1-ol(assumed stereochemistry): white solid, 40 mg (9%). M.p: 200-202° C.HPLC (UV 254 nm): 99.25% purity. Chiral purity: e.e. %>99.99%.

Example 287:(1S,6R)-2,2-Difluoro-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexanol

A mixture of(1S,6R)-6-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-2,2-difluorocyclohexan-1-ol(Intermediate 46, 50 mg, 0.12 mmol, 1.00 eq.),1-methyl-4-[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole(53 mg, 0.18 mmol, 1.45 eq.), Pd(PCy₃)₂Cl₂ (11 mg, 0.01 mmol, 0.12 eq.)and K₃PO₄ (62 mg, 0.28 mmol, 2.27 eq) in dioxane (2 mL) and water (0.5mL) was heated for 3 h at 100° C. under nitrogen atmosphere in a sealedtube. The resulting mixture was then concentrated under vacuum. Theresidue was diluted with DCM. The aqueous phase was separated andextracted twice with DCM. Combined organic phases were washed withbrine, dried over magnesium sulfate, filtered and concentrated.Purification by Prep-HPLC (XBridge BEH130 Prep C18 OBD Column) affordedthe title compound as a white solid (35 mg, 61%). LC/MS (Column:Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to100% B in 2.1 min, hold 0.5 min; 220 nm): (purity) 99.9%; [M+H]+ Cac.466.3; found 466.3. 1H NMR (300 MHz, DMSO-d6, ppm) 8.48 (s, 1H), 8.23(s, 1H), 8.17 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 7.84 (s,1H), 7.78 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.36(d, J=7.6 Hz, 1H), 5.62 (d, J=6.4 Hz, 1H), 4.31 (m, 1H), 3.92 (s, 3H),3.89 (s, 3H), 2.13 (m, 2H), 1.75 (m, 2H), 1.53 (m, 2H).

Example 288 and 289:(1R,2S,3S)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cycloheptane-1,2-dioland(1S,2R,3R)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cycloheptane-1,2-diolStep 1:N-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(Racemic—Relative Stereochemistry)

The title compound was obtained following the procedure described forexample 287 fromN-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(Intermediate 51, 180 mg, 0.43 mmol, 1.00 eq.) as an yellow oil (220 mg,92%). LC/MS (Column: Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile PhaseA: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 100% B in 2.1 min, hold 0.5 min; 220 nm):(purity) 90.0%; [M+H]+ Cac. 500.3; found 500.0.

Step 2:(1R,2S,3S)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cycloheptane-1,2-dioland(1S,2R,3R)-3-{5-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cycloheptane-1,2-diol

A solution of conc. HCl (0.75 mL, 24.68 mmol, 62 eq.) in MeOH (1 mL) wasadded dropwise to a solution ofN-[(3aS,4S,8aR)-2,2-dimethyl-octahydrocyclohepta[d][1,3]dioxol-4-yl]-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-amine(220 mg, 0.40 mmol, 1.00 eq.) in MeOH (2 mL) maintained at 0° C. Theresulting solution was stirred for 16 h at RT. The pH value of thesolution was adjusted to 8 by addition of ammonia. The reaction mixturewas concentrated under vacuum and purified by flash chromatography(H₂O:MeOH, 1:1) to afford the title compound as a racemic mixture (130mg). The two enantiomers were separated by Chiral-Prep-HPLC (ChiralpakIC, MeOH).

First eluting isomer: 50 mg (31%). m.p.: 176-178° C. LC/MS (Column:Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to100% B in 2.1 min, hold 0.5 min; 220 nm): (purity) 99.1%; [M+H]+ Cac.460.2; found 460.0. 1H NMR (300 MHz, Chloroform-d) 8.50 (s, 1H), 8.20(d, J=8.0 Hz, 2H), 7.86 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.56 (d,J=10.6 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.00 (d, J=7.4 Hz, 1H),4.62-4.42 (m, 1H), 4.12 (d, J=2.8 Hz, 1H), 4.10-4.01 (m, 1H), 3.97 (d,J=8.0 Hz, 5H), 2.21-2.01 (m, 1H), 1.93 (q, J=9.8, 9.1 Hz, 1H), 1.86-1.76(m, 3H), 1.69 (d, J=6.3 Hz, 3H), 1.63-1.45 (m, 2H).

Second eluting isomer: 59 mg (31%). m.p.: 176-178° C. LC/MS (Column:Shim-pack XR-ODS, 2.0*50 mm, 1.6 um; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to100% B in 2.1 min, hold 0.5 min; 220 nm): (purity) 98.6%; [M+H]+ Cac.460.2; found 460.0.

Example 290:(1S,2R,6S)-2-Fluoro-6-{5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cyclohexanol(Racemic—Relative Configuration) Step 1:(1S,2S,3S)-2-(methoxymethoxy)-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexylAcetate (Racemic—Relative Stereochemistry)

The title compound was obtained following the procedure described forexample 287 from(1S,2S,3S)-3-[[2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino]-2-(methoxymethoxy)cyclohexylacetate (Intermediate 54, racemic, 330 mg, 0.72 mmol, 1.00 eq.) as ayellow solid (480 mg, 100%). MS: m/z=532.5 [M+H]+.

Step 2:(1S,2S,3S)-2-(methoxymethoxy)-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexan-1-ol(Racemic—Relative Stereochemistry)

A solution of(1S,2S,3S)-2-(methoxymethoxy)-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexylacetate (racemic, 480 mg, 0.81 mmol, 1.00 eq.) and sodium hydroxide (100mg, 2.45 mmol, 3.02 eq.) in THF (10 mL) and water (2 mL) was stirred for2 h at 25° C. It was then concentrated under reduced pressure anddiluted with water (20 mL). The resulting mixture was extracted with DCM(3×10 mL). Combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. Purificationby flash chromatography on silica (MeOH/DCM, 1:100 to 1:25) afforded thetitle compound as a brown solid (340 mg, 77%). MS: m/z=490.4 [M+H]⁺.

Step 3:N-[(1S,2S,3R)-3-fluoro-2-(methoxymethoxy)cyclohexyl]-5-(1-methyl-H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-amine(Racemic—Relative Stereochemistry)

A solution of(1S,2S,3S)-2-(methoxymethoxy)-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexan-1-ol(racemic, 340 mg, 0.56 mmol, 1.00 eq., 80% purity) in dichloromethane (1mL) was added dropwise to a solution of XtalFluor-E (195 mg, 0.83 mmol,1.50 equiv, 98% purity) in DCM (10 mL) maintained at 0° C. undernitrogen atmosphere. TEA. 3HF (147 mg, 0.89 mmol, 1.61 equiv, 98%purity) was then added dropwise to the resulting mixture at 0° C. Thereaction mixture was warmed to RT and stirred for another 1 h. It wasthen quenched by the addition of 20 mL of H₂O and extracted with DCM(3×10 mL). Combined organic layers were washed with brine (1 mL), driedover anhydrous sodium sulfate, filtered and concentrated. Purificationby flash chromatography on silica (MeOH/DCM, 1:100 to 1:20) afforded thetitle compound as a yellow solid (144 mg, 47%). MS: m/z=492.4 [M+H]⁺.

Step 4:(1S,2R,6S)-2-fluoro-6-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclohexan-1-ol(Racemic—Relative Stereochemistry)

A saturated solution of HCl (g) in dioxane (2 mL) was added to asolution ofN-[(1S,2S,3R)-3-fluoro-2-(methoxymethoxy)cyclohexyl]-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-amine(racemic, 139 mg, 0.28 mmol, 1.00 eq.) in dioxane (2 mL). The reactionmixture was stirred for 2 h at 25° C. The pH value of the solution wasadjusted to 7 with saturated sodium bicarbonate (aq.) and the resultingmixture was concentrated under vacuum. The residue was diluted with 10mL of DCM. The solids were filtered out. The filtrate was concentratedunder vacuum and the crude product (100 mg) was purified by prep-HPLC[SHIMADZU: Column: XBridge BEH130 Prep C18 OBD Column, 19×150 mm, 5 μm,13 nm; Mobile phase: waters (10 mmol/L NH₄HCO₃) and ACN (35% to 41% in10 min); Detector: UV 254 nm] to afford the title compound as a whitesolid (73 mg, 56%). m.p.: 116-120° C. HPLC (UV 254 nm): 97.85% purity.MS: m/z=448.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 8.51 (s, 1H),8.26 (s, 1H), 8.17-8.14 (m, 2H), 8.07 (s, 1H), 7.86 (s, 1H), 7.77 (s,1H), 7.69-7.63 (m, 1H), 7.50-7.43 (m, 1H), 5.90 (d, J=7.7 Hz, 1H), 5.54(d, J=4.8 Hz, 1H), 4.87-4.67 (m, 1H), 4.52-4.42 (m, 1H), 4.06-4.02 (m,1H), 3.93 (s, 3H), 3.88 (s, 3H), 1.82-1.56 (m, 6H).

Example 291:(1R,2S,7S)-2-Methylamino-7-{5-(1-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-4-ylamino}-cycloheptanol(Racemic—Relative Configuration) Step 1:N-(cyclohept-2-en-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-amine

The title compound was obtained following the procedure described forexample 287 from2-chloro-N-(cyclohept-2-en-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(Intermediate 56, 12 mg, 0.04 mmol, 1.00 eq.) as a yellow oil (10 mg,59%). LC/MS: [M+H]+ Cac. 426.2; found 426.0.

Step 2:5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-[(1S,7R)-8-oxabicyclo[5.1.0]octan-2-yl]pyrimidin-4-amine(Racemic—Relative Stereochemistry)

mCPBA (156 mg, 0.86 mmol, 3.12 eq.) was added portion wise to a solutionofN-(cyclohept-2-en-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-amine(130 mg, 0.27 mmol, 1.00 eq.) maintained at 0° C. and under nitrogenatmosphere in DCM (8 mL). Sodium bicarbonate (78 mg, 0.88 mmol, 3.21eq.) was added and the resulting solution was stirred for 6 h at 20° C.After dilution with DCM, the mixture was then washed with sodiumcarbonate aq. and brine. Organic layer was dried over anhydrous sodiumsulfate, filtrated and concentrated. Purification by flashchromatography on silica (DCM:MeOH, 20:1) afforded the title compound asan yellow oil (70 mg, 46%). LC/MS: [M+H]+ Cac. 442.2; found 442.0

Step 3:(1R,2S,7S)-2-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]-7-(methylamino)cycloheptan-1-ol(Racemic—Relative Stereochemistry)

A solution of CH₃NH₂ (310 mg, 9.98 mmol) in MeOH (5 mL) was added over5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-[(1S,2S,7R)-8-oxabicyclo[5.1.0]octan-2-yl]pyrimidin-4-amine(racemic, 65 mg, 0.13 mmol, 1.00 equiv, 85% purity). The resultingreaction mixture was stirred for 36 h at 80° C. It was then concentratedunder vacuum and the crude product (50 mg) was purified by prep-HPLC[SHIMADZU: Column: XBridge BEH130 Prep C18 OBD Column, 19×150 mm, 5 μm,13 nm; Mobile phase: waters (10 mmol/L NH₄HCO₃) and ACN (27% to 34% in 8min); Detector: UV 254 nm] to afford the title compound (10 mg, 16%yield) as an off-white solid. m.p. 120-122° C. HPLC (UV 254 nm): 96.53%purity. MS: m/z=473.2 [M+H]⁺; 1H NMR (400 MHz, Chloroform-d, ppm): δ8.46 (s, 1H), 8.21-8.17 (m, 2H), 7.85 (s, 1H), 7.73 (s, 1H), 7.66 (s,1H), 7.61 (s, 1H), 7.58-7.53 (m, 1H), 7.48-7.42 (m, 1H), 5.93 (d, J=6.8Hz, 1H), 4.53 (brs., 1H), 4.13-4.09 (m, 1H), 3.94 (s, 3H), 3.00-2.92 (m,1H), 2.63 (s, 3H), 2.01-1.92 (m, 2H), 1.85-1.74 (m, 5H), 1.51-1.40 (m,1H).

Example 292: Enzymatic Assays

IRAK1 Enzymatic Assay

IRAK1 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712)).In this assay, IRAK-1 hydrolyses ATP and autophosphorylates. Measurementof IRAK-1 inhibition was performed in streptavidin coated 384wellFlashPlate (PerkinElmer #SMP410A).

His-TEV-IRAK-1 (15 ng/well), ATP (1 μM, [33P]ATP 0.25 μCi/well) andcompounds in DMSO (range of concentrations from 20 M to 1 nM) orcontrols (2% DMSO) were incubated for 3 hours at 30° C. in assay buffer:Hepes pH7.0 50 mM, Fatty acid-free BSA 0.1%, Dithiothreitol DTT 2 mM,MgCl2 10 mM, EGTA 0.5 mM, Triton-X-100 0.01%. Kinase reaction wasstopped by addition of EDTA. Supernatant was discarded, plates werewashed three times with 150 mM NaCl and radioactivity was then measuredin a Microbeta Trilux reader.

IRAK4 Enzymatic Assay

IRAK4 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712).IRAK4 hydrolyses ATP, autophosphorylates and phosphorylates aSerine/Threonine generic peptidic substrate (STK: 61ST1BLC from CisBioInternational based in Bagnols/Cèze FR).

Measurement of IRAK-4 inhibition was performed in streptavidin coated384well FlashPlate (PerkinElmer #SMP410A). His-TEV-IRAK4 (20 ng/well),ATP (2 μM, [³³P]ATP 0.25 Ci/well), STK1-biotin peptide (300 nM) andcompounds in DMSO (range of concentrations from 20 M to 1 nM) orcontrols (2% DMSO) were incubated for 3 hours at 30° C. in assay buffer:Hepes pH7.0 50 mM, Fatty acid-free BSA 0.1%, Dithiothreitol DTT 2 mM,MgCl2 10 mM, EGTA 0.5 mM, Tween-20 0.01%, MnCl2 5 mM.

Kinase reaction was stopped by addition of EDTA. Supernatant wasdiscarded, plates were washed three times with 150 mM NaCl andradioactivity was then measured in a Microbeta Trilux reader.

TLR7 Induced IL-6 in Human PBMC's

Human PBMC assay was used as one of the functional assay a to monitorthe activity of of IRAK1 and IRAK4 small molecule inhibitors on TLR7induced IL-6 secretion in human mononuclear cells (PBMC's). Human PBMCswere prepared from buffy coats (whole blood enriched with leukocytes andplatelets) obtained from healthy volunteers used either fresh or frozenare plated in assay media (RPMI+2% P/S/L-glu+10% HI-FBS) and pre-treatedwith compounds in DMSO/media (range of concentrations from 25 uM to 0.4nM) or controls (0.25% DMSO) for 30 minutes at 37° C. in assay media.Following pre-treatment with IRAK1 and IRAK4 inhibitors, PBMC's werestimulated with TLR7 specific ligand (2 uM) overnight (16-18 hrs) at 37°C. After incubation supernatant was transferred to 384 well PEAlphaPlate-384 (6005350) and IL-6 is quantified using Perkin Elmer IL-6Alpha LISA kit (AL223C). Plates were read on an Envision® plate readerwith Alpha Technology®.

Results are given in the following table.

TLR7 induced IL- IRAK1 IRAK4 6 secretion in Compound IC50 IC50 hPBMC's(IC50) 1 * *** ** 2 ** *** NT 3 ** * NT 4 ** ** NT 5 ** * NT 6 * ** NT 7*** *** ** 8 * ** NT 9 ** *** ** 10 *** *** ** 11 * *** ** 12 * * NT 13*** *** ** 14 **** **** NT 15 *** **** *** 16 *** **** *** 17 * **** ***18 * **** *** 19 * *** ** 20 *** ** *** 21 ** **** ** 22 *** **** ***23 * ** NT 24 * ** NT 25 * ** NT 26 * * NT 27 ** *** NT 28 **** **** ***29 ** *** NT 30 *** *** NT 31 *** *** NT 32 *** **** ** 33 ** ** NT 34 *** NT 35 *** *** ** 36 ** *** *** 37 ** *** ** 38 ** *** * 39 * ** NT40 * ** NT 41 *** *** ** 42 *** *** *** 43 *** *** ** 44 *** **** *** 45** *** ** 46 *** *** * 47 ** *** * 48 *** *** * 49 *** *** * 50 *** ***** 51 * ** NT 52 *** **** ** 53 *** **** ** 54 *** *** ** 55 *** **** **56 * **** ** 57 *** *** * 58 ** ** NT 59 * *** NT 60 ** *** ** 61 * ***NT 62 ** *** ** 63 *** **** ** 64 ** *** NT 65 *** **** *** 66 **** ******* 67 * *** NT 68 ** *** NT 69 * *** NT 70 *** ** NT 71 * * NT 72 * **NT 73 ** ** NT 74 ** *** NT 75 * * NT 76 ** *** * 77 * *** ** 78 ** ***NT 79 *** *** NT 80 * *** NT 81 ** *** * 82 ** *** NT 83 ** *** *** 84** *** * 85 * *** ** 86 ** **** * 87 ** **** ** 88 * *** NT 89 * ** NT90 * * NT 91 * * NT 92 * * NT 93 *** **** *** 94 *** **** ** 95 * ****NT 96 ** **** NT 97 *** **** ** 98 ** *** NT 99 *** **** *** 100 ** ***NT 101 ** **** *** 102 ** *** NT 103 ** **** NT 104 ** *** NT 105 * ***NT 106 * **** NT 107 *** *** *** 108 *** **** *** 109 * *** NT 110 * **NT 111 *** **** NT 112 ** *** ** 113 *** **** ** 114 ** *** NT 115 * ****** 116 * *** NT 117 * *** NT 118 ** **** ** 119 ** *** * 120 *** *** NT121 * *** NT 122 * *** NT 123 *** **** *** 124 * *** NT 125 * *** ***126 * *** NT 127 * **** *** 128 *** **** *** 129 *** **** *** 130 ** ***NT 131 ** **** ** 132 *** **** *** 133 *** **** *** 134 **** **** ****135 *** **** *** 136 *** **** ** 137 *** **** *** 138 ** **** ** 139 ****** NT 140 ** *** NT 141 ** *** ** 142 * ** NT 143 *** **** *** 144 **** NT 145 * *** NT 146 * **** ** 147 * **** NT 148 * *** NT 149 ******* *** 150 * *** NT 151 *** **** *** 152 *** **** *** 153 *** **** ***154 * *** NT 155 * **** NT 156 *** **** *** 157 *** **** NT 158 *** ****NT 159 * **** NT 160 *** **** NT 161 **** **** *** 162 *** **** *** 163*** **** NT 164 ** **** NT 165 *** **** NT 166 *** **** NT 167 ** ****** 168 * **** NT 169 *** **** * 170 *** **** ** 171 **** **** ** 172 ******* NT 173 * *** NT 174 *** **** NT 175 *** *** NT 176 ** **** NT 177*** **** NT 178 *** *** NT 179 *** **** ** 180 *** **** NT 181 *** ****** 182 **** **** *** 183 *** **** ** 184 *** **** *** 185 ** **** ** 186**** **** *** 187 **** **** *** 188 **** **** ** 189 * * NT 190 ******** ** 191 * *** NT 192 ** **** NT 193 * *** NT 194 *** **** *** 195**** **** ** 196 *** *** ** 197 * *** NT 198 ** **** NT 199 *** **** ***200 ** *** NT 201 ** **** NT 202 ** *** NT 203 ** *** NT 204 *** ******* 205 *** **** NT 206 * *** NT 207 NT 208 *** **** *** 209 **** ******* 210 *** **** *** 211 *** *** ** 212 * *** NT 213 **** **** *** 214 ***** ** 215 *** **** *** 216 *** **** *** 217 *** **** ** 218 ** *** NT219 *** **** ** 220 *** **** NT 221 *** **** *** 222 *** *** NT 223 ******* NT 224 ** **** NT 225 *** **** *** 226 * *** NT 227 *** **** NT228 * ** NT 229 * *** NT 230 * ** NT 231 * ** NT 232 *** **** NT 233 ******* *** 234 ** **** NT 235 ** *** NT 236 ** *** NT 237 ** *** NT 238*** **** *** 239 *** *** *** 240 * *** NT 241 ** *** NT 242 *** **** ***243 ** **** *** 244 *** **** *** 245 **** **** *** 246 * ** NT 247 ***** NT 248 *** **** *** 249 ** *** NT 250 ** *** NT 251 * ** NT 252 ******* NT 253 **** **** *** 254 **** **** **** 255 *** *** NT 256 ** ****** 257 *** **** ** 258 * *** NT 259 * *** NT 260 *** *** ** 261 ** ***NT 262 *** **** ** 263 * ** NT 264 * ** NT 265 *** **** * 266 **** ******* 267 *** **** *** 268 **** **** **** 269 *** **** *** 270 **** ******** 271 *** **** ** 272 *** **** ** 273 *** **** *** 274 * *** NT 275*** **** *** 276 **** **** *** 277 * *** NT 278 **** **** *** 279 **** * 280 *** **** ** 281 * **** ** 282 ** *** * 283 ** ** ** 284 ****** *** 285 *** **** *** 286 *** **** *** 287 *** **** ** 288 **** ******** 289 * **** *** 290 NT 291 NT * IC₅₀ > 5 μM ** IC₅₀ ranges from 1μM-5 μM *** IC₅₀ ranges from 0.1 μM-1.0 μM **** IC₅₀ < 0.1 μM NT NotTested

Example 293: Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: X is CR or N; Ais O, S, SO₂, SO, —NRC(O), —NRSO₂, or N(R); or A is absent; R³ is H,C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; or R³ is halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; or when A is —NRC(O), —NRSO₂, or N(R);then R and R³, together with the atoms to which each is attached, mayform a 3-7 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted; X′ is CR or N; Ring Z is a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; R¹ is —R, halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; R^(a) is absent, —R, halogen,-haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; Ring Y is an optionallysubstituted pyridyl, pyrazole or thiadiazole; R² is —R, halogen,-haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; R^(b) is absent, —R,halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; each R isindependently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; or two Rgroups on the same atom are taken together with the atom to which theyare attached to form a C₃₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted; wherein when X is N and A is absent, then R³is not H.
 2. The compound of claim 1, wherein X is CH.
 3. The compoundof claim 1, wherein X is N.
 4. The compound of claim 1, wherein A is Oor N(R), or A is absent.
 5. The compound of claim 1, wherein R³ is H,C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; or R³ is -haloalkyl, —C(O)R,—CO₂R, or —C(O)N(R)₂.
 6. The compound of claim 5, wherein R³ is C₁₋₆aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated or partially unsaturatedcarbocyclic ring, or a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted.
 7. The compound of claim 1,wherein A-R³ is —H, —CH₃, —CF₃,


8. The compound of claim 1, wherein Ring Z is:

wherein X is O, S or NR¹; Y is C or N; and T is C or N.
 9. The compoundof claim 8, wherein Ring Z is


10. The compound of claim 1, wherein Ring Y is


11. The compound of claim 1, of formula I-b,

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, of formula I-c,

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, selected from:


14. A pharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable adjuvant, carrier, or vehicle.
 15. A methodfor treating a disorder is selected from Rheumatoid Arthritis, SystemicLupus Erythematosus, Lupus nephritis, Multiple Sclerosis, Alzheimer'sdisease, Parkinson's disease, and Cancer, in a patient in need thereof,comprising the step of administering to said patient a compound ofclaim
 1. 16. A method for treating cancer in a subject, comprising thestep of administering to said subject a compound of claim 1 or aphysiologically acceptable salt thereof.
 17. A process for manufacturinga compound of formula I according to claim 1, comprising the steps of:reacting a compound of formula (A):

with

wherein X, Y, A, R, R^(a), R^(b), R² and R³ are as defined in claim 1;to provide a compound of formula (B):

and reacting the compound of formula (B) with

wherein Z and R¹ are as defined in claim 1; to provide a compound offormula I of claim 1.